Mechanism of resistance to target therapy
83
MECCANISMI DI RESISTENZA AI FARMACI MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC NEL mRCC Michele Guida Dipartimento di Oncologia Medica Istituto dei Tumori Bari Otranto 27 gennaio 2012
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resistance mechanism to target therapy
Transcript of Mechanism of resistance to target therapy
MECCANISMI DI RESISTENZA AI FARMACIMECCANISMI DI RESISTENZA AI FARMACI
NEL mRCCNEL mRCC
Michele GuidaDipartimento di Oncologia Medica
Istituto dei Tumori Bari
Otranto 27 gennaio 2012
Drugs Resistance in mRCCDrugs Resistance in mRCC
1 Definition of resistance
2 The resistance mechanisms
3 How can we overcome the resistance mechanisms
Drugs Resistance in mRCCDrugs Resistance in mRCC
1 Definition of resistance
2 The resistance mechanisms
3 How can we overcome the resistance mechanisms
Drugs Resistance DefinitionDrugs Resistance Definition
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary and Secondary ResistancePrimary and Secondary Resistance
Adaptive (evasive) resistance
Intrinsic non-responsiveness
2008
Pattern of Response to Available Therapy in mRCCPattern of Response to Available Therapy in mRCC
Rini Urologic Oncology 2008Rini Lancet Oncol 2009
10-15 of pts 50-60 of pts30 of pts
about 6 months about 12 months
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistance in mRCCDrugs Resistance in mRCC
1 Definition of resistance
2 The resistance mechanisms
3 How can we overcome the resistance mechanisms
Drugs Resistance in mRCCDrugs Resistance in mRCC
1 Definition of resistance
2 The resistance mechanisms
3 How can we overcome the resistance mechanisms
Drugs Resistance DefinitionDrugs Resistance Definition
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary and Secondary ResistancePrimary and Secondary Resistance
Adaptive (evasive) resistance
Intrinsic non-responsiveness
2008
Pattern of Response to Available Therapy in mRCCPattern of Response to Available Therapy in mRCC
Rini Urologic Oncology 2008Rini Lancet Oncol 2009
10-15 of pts 50-60 of pts30 of pts
about 6 months about 12 months
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistance in mRCCDrugs Resistance in mRCC
1 Definition of resistance
2 The resistance mechanisms
3 How can we overcome the resistance mechanisms
Drugs Resistance DefinitionDrugs Resistance Definition
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary and Secondary ResistancePrimary and Secondary Resistance
Adaptive (evasive) resistance
Intrinsic non-responsiveness
2008
Pattern of Response to Available Therapy in mRCCPattern of Response to Available Therapy in mRCC
Rini Urologic Oncology 2008Rini Lancet Oncol 2009
10-15 of pts 50-60 of pts30 of pts
about 6 months about 12 months
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistance DefinitionDrugs Resistance Definition
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary and Secondary ResistancePrimary and Secondary Resistance
Adaptive (evasive) resistance
Intrinsic non-responsiveness
2008
Pattern of Response to Available Therapy in mRCCPattern of Response to Available Therapy in mRCC
Rini Urologic Oncology 2008Rini Lancet Oncol 2009
10-15 of pts 50-60 of pts30 of pts
about 6 months about 12 months
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Primary and Secondary ResistancePrimary and Secondary Resistance
Adaptive (evasive) resistance
Intrinsic non-responsiveness
2008
Pattern of Response to Available Therapy in mRCCPattern of Response to Available Therapy in mRCC
Rini Urologic Oncology 2008Rini Lancet Oncol 2009
10-15 of pts 50-60 of pts30 of pts
about 6 months about 12 months
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Pattern of Response to Available Therapy in mRCCPattern of Response to Available Therapy in mRCC
Rini Urologic Oncology 2008Rini Lancet Oncol 2009
10-15 of pts 50-60 of pts30 of pts
about 6 months about 12 months
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistence in mRCCDrugs Resistence in mRCC
Influence of patient risk score and prior therapyInfluence of patient risk score and prior therapy
Setting Author Drug primary resistance
1a linePts with good-intermediate prognosis
Motzer 2007Ranpura 2010 Sunitinib 224
Su 2010 Sorafenib 226
1a linePts with poor prognosis
Hudes 2007 Temsirolimus 33
2a line
Motzer 2008Everolimus after TKI
20
Su 2010Sunitinib afterSorafenib
522
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Percentage of pts who receives a 2d line therapyPercentage of pts who receives a 2d line therapy
First line Second linePredictive
factors
DrugAuthor N Pts TerapiaN Pts
()
SunitinibMotzer et al JCO 2009
375(sunitinib arm)
Anti-VEGFanti-mTOR
182 (56)
-
Beva + IFNEscudier et al JCO 2010
325(beva-IFN arm)
TKI180 (55)
-
TKI (vari studi)Vikers et alUrology 2010
645Anti-VEGFanti-mTOR
216 (30)
Basal PS
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistance in mRCCDrugs Resistance in mRCC
Conclusive ConsiderationsConclusive Considerations
About 30 of mRCC has an innate resistance to all available
treatments
Resistance to TKi seems to be independent from the type of TKi used
Prior treatment with Sunitinib significantly increased the risk of resistance to Sorafenib
Resistance is present also in mTORi treated pts
Resistance is correlated to the pts characteristics (histology risk score) and to the type of prior therapy
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
22 The resistance mechanismsThe resistance mechanisms
3 How can we overcome the resistance mechanisms
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Resistance Resistance Mechanisms Mechanisms in mRCCin mRCC
1 The ldquoangiogenic escaperdquo to anti‑VEGF treatment is dependent
both on cancer cell phenomena or endothelial cell phenomena
2 Hypoxia is a known inducer of angiogenic response in a wide
variety of tumors
3 Nevertheless it is strongly believed that hypoxia is also the key
mechanism of angiogenic escape
4 When angiogenesis is inhibited tumors are in a hypoxic state
and develop new alternative pathways to guarantee their further
growth
General considerations
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Primary Resistance to TKI in mRCCPrimary Resistance to TKI in mRCC
Which mechanisms Which mechanisms
1 These cases have already activated one or more
mechanisms of resistance not in response to
therapy but in response to the selective pressure
of their microenvironment
2 Probably these cases of mRCC are not sustained
(not only) by angiogenesis mechanisms
2008
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Primary ResistancePrimary Resistance
Drugs Resistence in mRCCDrugs Resistence in mRCC Which mechanisms Which mechanisms
bull Upregulation of alternate proangiogenic pathways (FGFR IL-8 insulin-like GFR ephrins and angiopoietins)
bull Pre-existing inflammatory cell-mediated vascular protection (myeloid cell)
bull Hypovascularity and indifference toward angiogenesis inhibitors (desmoplastic stroma)
bull Co-option of normal vessels without requisite angiogenesis
Sleijfer et al Oncologist 2007Blanke et al J Clin Oncol 2008Huang et al Cancer Res 2010
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drugs Resistance MechanismsDrugs Resistance Mechanisms
PRIMARY (also ldquorefractorinessrdquo or ldquointrinsic responsivenessrdquo)
Lack of efficacy to TKI from the start of therapy
SECONDARY (also ldquoacquiredrdquo or ldquoadaptiverdquo or ldquoevasiverdquo or ldquoangiogenesis escaperdquo)
Arises upon the initial response to TKI lasting for a period of time of variable length
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Hypoxia the key of the escape
Casanovas et al Cancer Cell 20058299-309
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Angiogenic Escape (II)
Paez-Ribes et al Cancer Cell 2009
ldquoAccelerated metastasis after short-term treatment
with a potent inhibitor of tumor angiogenesisrdquo
ldquoAntiangiogenic therapy elicits malignant
progression of tumors to increased local invasion and
distant metastasisrdquo
Ebos et al Cancer Cell 2009
Experimental
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Neoplastic Evolution and Mechanisms Neoplastic Evolution and Mechanisms of Angiogenic Escapeof Angiogenic Escape
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
It has been reported that the endothelial cell inhibition mediated by TKi can be rescued by 19 pro-angiogenic factors secreted by the tumoral vasculature
In particular FGF2 and IL-8 support endothelial proliferation and de novo tubule formation in the presence of sunitinib
Faivre et al Nat Rev Drug Discov 2007 6(9)734-745 Review
Angiogenic Escape in mRCC Angiogenic Escape in mRCC
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Development of Resistance Development of Resistance Angiogenic Escape (I)Angiogenic Escape (I)
Adapted from Casanovas et al Cancer Cell 20058299-309
VEGF PIGF
No angiogenesis
Hypoxia
Cancer cellsVEGF inhibitors
Early Phase Response to Anti-VEGF Treatment
Endothelial Cell
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGFIL-8 and other
factors
Late Phase Escape to Anti-VEGF Treatment
HIFHIF
VEGF inhibitors
FGF fibroblast growth factor HIF hypoxia-inducible factor PlGF placental growth factor VEGF vascular endothelial growth factor
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
bull FGFR is highly expressed in RCC (80 of pts)
bull High levels of bFGF are reported in patients with disease progression
bull Increased expression of FGFR1 is associated with a shorter progression free survival
In human
Welti et al Oncogene 2011 30(10)1183-1193Tsimafeyeu Iet al J Clin Oncol 2815s 2010 (suppl abstr 4621)Ho Th et al ASCO meeting 2011 J Clin Oncol 29 2011 (suppl abstr e15015)
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Angiogenic EscapeIL-8 mediates resistance to SunitinibIL-8 mediates resistance to Sunitinib
In Xenograft modelsIn Xenograft models
The resistance to sunitinib is associated to a higher microvessel The resistance to sunitinib is associated to a higher microvessel density indicating an escape from antiangiogenesis and IL-8 levelsdensity indicating an escape from antiangiogenesis and IL-8 levels
Huang et al Cancer Res 2010
IL-8
Sunitinib responsive
Sunitinibresistentrefractory + Ac anti IL-8
Conclusions IL-8 mediates resistance to sunitinib and could represent a candidate target to reverse acquired or intrinsic resistance to sunitinib
Resensitized tumor
IL-8
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
In human
bull Higher levels of IL-8 were associated with shorter progression free survival in mRCC patients treated in phase III trials of pazopanib
Liu et al ASCO 2011
bull Higher expression of IL-8 on the tumor tisuue (IIC) is associated with resistance to sunitinib
Huang et al Cancer Res 2010
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The epithelial-to-mesenchymal transition process
Secondary resistance to anti-angiogenic Secondary resistance to anti-angiogenic therapiestherapies
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The epithelial-to-mesenchymal transition process
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The epithelial-to-mesenchymal transition process
Mechanisms of Disease epithelialndashmesenchymal transitionmdashdoes cellular plasticity fuel neoplastic progressionEva A Turley Mandana Veiseh Derek C Radisky and Mina J BissellNature Clinical Practice Oncology 2008
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The epithelial to mesenchymal transition processWhat significance
Secondary resistance to anti-angiogenic therapies
bull Sarcomatoid phenotype is observed across all histological subtypes and associated with a poorer prognosis
bull It is a potentially transientreversible phenotype of epithelial cancers
bull Epithelial-mesenchymal transition process acquires resistance to anti-angiogenic inhibitors in pts with renal cell carcinoma
Hugo H Ackland ML Blick T et al Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression J Cell Physiol 2007 213374ndash383Hammers HJ Verheul HM Salumbides B et al Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma evidence from a xenograft study Mol Cancer Ther 2010 91525-1535Klymkowsky MW Savagner P Epithelial-mesenchymal transition A cancer researchers conceptual friend and foe Am J Pathol 2009 1741588ndash1593
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The epithelial to mesenchymal transition processMain characteristics
Secondary resistance to anti-angiogenic therapies
Bostrom et al Hum Pat 2011Giron-Michel et al Bull Cancer 2011Khawam et al Cancer Res 2009
bull Higher proliferative index
bull Transforming growth factor β1 exposure of in vitro cultured primary ccRCC cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid phenotype
bull IL-15 is a major regulator of epithelial homeostasis of the cell-microenvironment interactions in human renal cancer
bull Loss of the epithelial markers E-cadherin and ZO-1
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
A specific gene expression signature characterizes metastatic potential in ccRCC
Sanimyatav et al J Urol 2011
bull Transcriptional profiling of 16 primary metastatic and 18 non-metastatic clear cell renal cell carcinomas with microarrays
bull Possibility of defining the metastatic potential of primary clear cell renal cell carcinoma based on a select number of genes even
bull Potential biomarkers for metastatic clear cell renal cell carcinoma by gene expression analysis
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
The intratumoral heterogeneity and gene mutations
Secondary resistance to anti-angiogenic therapies
Lee AJ Endesfelder D Rowan AJ Walther A et al Chromosomal instability confers intrinsic multidrug resistance Cancer Res 2011 71(5)1858-70Navin N Kendall J Troge J et al Tumour evolution inferred by single-cell sequencing Nature 2011 472(7341)90-94
bull Due to this genomic instability it is strongly believed that resistance is a dynamic mechanism changing in different conditions (treatment pressure hypoxia pressure etc) and during the tumor growth
bull Some genes are hyperexpressed when there is resistance (gene encoding sphingosine kinase calvasculin chemokine receptor 4 (CXCR4) NNP1 arginase II hypoxia-inducible protein-2 (HIG2) and VEGF)
bull Other anti-angiogenic genes show reduced expression in resistant tumors (genes encoding cytokines associated with interferon-gamma in particular IP10 (CXCL10) and Mig (CXCL9))
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Working ModelFactors Associated With Resistance
Antiangiogenic ProangiogenicProgrowth
-IL10-IFN
-VEGF-Ang2-IL8-MMP1-uPAR-Calvasculin-Arginase-TSP
Atkins M et al ASCO GU Symposium 2008 Abstract
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Factors Associated With Resistance in mRCC
Clinical- Poor risk pts- Histology non clear- Prior TKi
Huang et al Cancer Res 2010
Laboratory- levels of IL-8 IL-15 (proangiogenic)- level of HIF- Level of FGF- level of CA IX ()
Bio-molecular- Specific mutation- Gene profiling- hellip
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Primary resistance
- Alternative pro-angiogenic pathways mediated by FGFR interleukin-8 (IL-8) insulin-like GFR ephrins and angiopoietins
- Non angiogenic mechanisms- Pre-existing inflammatory cell-mediated vascular protection (myeloid cell) - Hypovascularity status with consequent indifference toward angiogenesis
inhibitors (desmoplastic stroma) - Co-option of normal vessels without requisite angiogenesis- Non clear cell histology
Secondary resistance
- New angiogenic wave induced by hypoxia determined by anti-angiogenic drugs
- Epithelial to mesenchymal transition- Intra-tumoral heterogeneity- Gene instability and gene iperexpression- Secondary mutations in tyrosine kinase receptors- Bone marrow-derived pro-angiogenic cells which can obviate the necessity of
VEGF signalling- Increasing of pericyte coverage of the tumour vasculature serving to support
its integrity and attenuate the necessity for VEGF-mediated survival- Access to normal tissue vasculature without obligate neovascularisation
Main mechanisms of primary and secondary resistance in mRCC
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Resistance to TKI in mRCCResistance to TKI in mRCC
1 Definition of resistance
2 The resistance mechanisms
33 How can we overcome the resistance How can we overcome the resistance mechanismsmechanisms
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull New drugs (denosumab hellip)
bull Re-challenge with TKiSequential therapies
bull Integrating the current treatment
ndash Combined therapies ()
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Resistance to anti-angiogenic therapies in mRCC
Zama IN Hutson TE Elson P et al Sunitinib rechallenge in metastatic renal cell carcinoma patients Cancer 2010 116(23)5400-5406
Rini BI Hutson HE Elson P et al Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma GU ASCO 2010 J Clin Oncol 2010 Abst 396
bullRe-challenge with anti-angiogenic agents could be a valid option for some pts
bullIt is thought that a ldquoholidayrdquo period from anti-VEGF therapies is able to determine a reacquired drug-sensitivity by clones become resistant to TKi drugs
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Michele Guida and Giuseppe Colucci
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling thereby effecting re-initiaton and continuance of tumour angiogenesis
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
1Activationupregulation of alternative pro-angiogenic signalling pathways
2Recruitment of bone marrow-derived pro-angiogenic cells which can obviate the necessity of VEGF signalling (circulating endotelial cells myeloid cell)
3 Incrising pericyte coverage of the tumour vasculature serving to support its integrity and attenuate the necessity for VEGF-mediated survival signalling
4Activation and enhancement of invasion and metastasis to provide access to normal tissue vasculature without obligate neovascularization
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Potential Mechanisms of Treatment Resistance In mRCC
Rini and Atkins 2010
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Potential mechanisms of VEGFR TKI Resistance
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
bull Using revertant drugs (IFN hellip)
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
RAD001 (everolimus) 10 mgd + BSCSCREEN
Placebo + BSC
Prim Endpt PFS
Sec Endpts Response Response
duration Survival Safety QoL
N = 3622 1
RAD001 Placebo
Upon Disease Progression
Randomize
Everolimus vs Placebo After Progression on a VEGFR-TKI
in mRCC (RECORD-1 study)
Phase III Study Design
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Stratification
Previous VEGFR-TKI1 or 2
MSKCC risk groupndash Favorable (29)ndash Intermediate (56) ndash Poor (15)
(N = 410)
Motzer et al The Lancet 2008
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Everolimus in mRCC (RECORD 1 study)
Independent prognostic factors for shorter OS
ndash low performance status
ndash high corrected calcium
ndash low hemoglobin
ndash prior sunitinib (P lt 01)
Motzer Escudier et al Cancer 2010
bull OR 2
bull SD 67
bull PFS 49 vs 19
bull OS 144 vs 144 (cross-over 80 of pts)
Final results and analysis of prognostic factors
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Benefit of everolimus after multiple lines of treatment
Escudier B et al ESMO 2008 abstr 720
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
mRCC about mTOR inhibition
What is the optimal time to use mTOR inhibitors in the
treatment sequence
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
FGFFGFR has been reported as one of the most
important escape pathway of anti-VEGFR therapies
Beta Fibroblast Growth Factor (FGFR) as a new Target for Anti-angiogenic Therapy
VEGFPIGF
Second wave ofangiogenesis
Cancer cells
Endothelial Cell
FGF and other factors
Late Phase Escape to Anti-VEGF Treatment
HIF
VEGF inhibitors
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Dofitinib a new multitarget agent
A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanomaK B Kim J Saro S S Moschos P Hwu A A Tarhini W Hwu G Jones Y Wang H Rupani and J M Kirkwood (ASCO 2008)
TKI258 (dovitinib lactate) in metastatic renal cell carcinoma (mRCC) patients refractory to approved targeted therapies A phase III dose finding and biomarker study
E Angevin J A Lopez A Pande C Moldovan M Shi J C Soria X Wang A Harzstark J Saro B Escudier ASCO 2009 Abst 3563
Study CTKI258A2202 A multicenter open-label phase II trial of dovitinib (TKI258) in FGFR1-amplified and nonamplified HER2-negative metastatic breast cancerF Andre J Baselga M J Ellis S A Hurvitz H S Rugo N C Turner E Argonza-Aviles S Lake M M Shi and O Anak (ASCO 2009)
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Dovitinib + BSCSCREEN
Sorafenib + BSC
Randomize
TKI 258 (Dovitinib) in mRCC
Phase III Study Design
third line therapy
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Selected Trials of Second-Line Agents After TKIBeva
Agent
AuthorPopulation
Study phase
N pts
ORSD
PFS(Mo)
OS(Mo)
Everolimus
vs placebo
Motzer et al Lancet lsquo08
TKI refractory III416 (21)
267
49
vs
18
14
vs 14
AxitinibRini et al JCO lsquo09
Sorafenib
refractoryII 62 2355 74 na
SunitinibRini et al JCO lsquo08
Bev
refractoryII 62 2375 71 102
SorafenibShepard et al ASCO lsquo08
Bevsunitinib refractory
II26
each 338 38
cross-over 80 of pts
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Second line therapy in mRCC For how many pts
First line Second line
TherapyAuthors N Pts Therapy N Pts ()
Sunitinib
Motzer et al JCO 2009
375
(sunitinib arm)
Anti-VEGFanti-mTOR 182 (56)
Beva + IFN (AVOREN study)
Escudier et al JCO 2010
325
(beva-IFN arm)TKI 180 (55)
TKI (various studies 7 centers)
Vikers et al Urology 2010645
Anti-VEGFanti-mTOR 216 (30)
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Estimated PFS of pts receiving sequential therapies
Escudier et al Cancer 2009
30-50 of pts 10 of pts 5pts
2a line 3a line 4a line
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Optimal Sequence May Depend on Responseto First Line Therapy
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Sequential therapy ongoing studies
Agent Sponsor phasePts
populationN
pts
Sunitinib - sorafenib
vs
Sorafenib - sunitinib
(SWITCH trial)
Bayer IIISequential
(I and II line)540
Pazopanib - Sunitinib
vs
Sunitinib - Pazopanib
GSK IIISequential
(I and II line)160
Sunitinib - Everolimus
vs
Everolimus - Sunitinib
(RECORD III trial)
Novartis IISequential
(I and II line)390
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
How can we overcome the resistance to TKI
bull Using non cross-resistant drugs
bull Re-challenge with TKISequential therapies
bull Integrating the current treatment
ndash Combined therapies
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
AgentRash or
Hand-Foot Reaction
Hypertension Cytopenia ProteinuriaGI or
Mucosal
Sunitinib Yes Yes Yes Yes Yes
Sorafenib Yes Yes Yes Yes
Bevacizumab Yes Yes
TemsirolimusEverolimus
Yes Yes Yes
Combination Drug Therapy Selected Adverse Events
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
bullBeva + TK inhibitors
bullTK inhibitors + mTOR inhibitors
bullBeva + mTOR inhibitors
Combined therapies in mRCC the future
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drug combinations
Study Pts
PFS (Mo)
OR Toxicity Comments
Beva + Sunitinib Garcia et al ASCO lsquo08
Phase I 31
(various) -
37 RCC 13 Mela 1 adrenal
Mild () Good
activity
Beva + Sunitinib Feldman Motzer Asco lsquo08
16
High (hypertension microangiop
Transient ischemic CNS)
Beva + Sorafenib Sosman et al ASCO lsquo08
Phase I-II 48 14
0 CR 25 PR 18 SD
High (hypertension
stomatitis hand-foot skin
reaction)
No full doses together
Escalating doses
Full dose Sorafenib + 50 Beva and reverse
Bevacizumab + TKI in mRCC Bevacizumab + TKI in mRCC
A negative experience
A negative experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Tumor Type Percentage of TumorsExpressing EGFR
References
Colorectal
Advanced Colorectal
25-77
75
Salomon (1995) Messa (1998)
Goldstein (2001)
Head and Neck 80-100 Salomon (1995) Grandis (1996)
Pancreatic
Advanced Stage
30-95
95
Salomon (1995) Uegaki (1997)Abbruzzese (2001)
NSCLC 40-80 Fujino (1996) Rusch (1997)Fontanini (1998)
Renal Carcinoma 50-90 Salomon (1995) Yoshida (1997)
Breast 14-91 Klijn (1992) Beckman (1996) Bucci (1997) Walker (1999)
Ovarian 35-70 Bartlett (1996)
Fischer-Colbrie (1997)
Glioma 40-63 Salomon (1995) Watanabe (1996)Rieske (1998)
Bladder 31-48 Salomon (1995) Chow (1997)
EGFR EXPRESSION IN SELECTED HUMAN TUMORSEGFR EXPRESSION IN SELECTED HUMAN TUMORS
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
Results
- OR 37
- SD 34
- Median PFS 11 moths
- Accettable toxicity (diarrea G3-4 in 14)
- No pharmacokinetic drug-drug interaction
Motzer RJ et al Am J Clin Oncol 2010
Conclusions ldquoSunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapyrdquo
42 pts- Sunitinib 375 or 50 mgd oral (4 weeks on 2 off)
- Gefitinib 250 mgd oral
A disappointing experience
A disappointing experience
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Is Combination Therapy Better
Angiogenesis Tumor cell proliferation
VEGF inhibitors-sunitinib-sorafenib-axitinib-pazopanib-bevacizumab
mTORakt inhibitors- temsirolimus- everolimus- perifosine
EGFR inhibitors - erlotinib- gefitinib- lapatinib- cetuximab
Inhibitors ofangiogenic escapemechanisms-dovitinib-AMG 386-M200
IFN
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Bevacizumab + mTOR inhibitor
A questionable experienceA questionable experience
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Drug combinations
Study Pts
PFS (Mo)
OR OS
(Mo) Toxicity
Beva + Everolimus
Whorf et al ASCO lsquo08
Phase II
59
11 (in 29 pretr
with TKI)
12
(first line) 23 PR 53 SD
- mild
Beva + Temsirolimus
Merchan et al JCO rsquo09 45 53 18 145 - acceptable
Bevacizumab + mTORI in mRCCBevacizumab + mTORI in mRCC
First and Second line
A questionable experienceA questionable experience
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Bevacizumab + mTOR inhibitor
Everolimus + Bevacizumab
Placebo
1deg Endpoint
PFSR 11Screen
Randomized phase III second line study (CALG study)
RECORD-2 randomized phase II first-line study
Everolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
Phase III randomized first-line study
Temsirolimus + Bevacizumab
Interferon alfa-2a + Bevacizumab
1deg Endpoint
PFSR 11Screen
822 pts
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Can the combination of Temsirolimus and Bevacizumab
improve the treatment of mRCC
Results of the randomized TORAVA phase II trial
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + mTOR inhibitor
First line therapy
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
bull Primary endpoint non-progression rate at week 48 gt 50 (42 to 46 previous studies) bull 160 patients required for 211 randomization
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
RESULTS
OutcomeTemsirolimusBeva
(n = 88)Sunitinib(n = 42)
BevaInterferon(n = 41)
48 ww non PDgt50
307 405 659
PFS (Mo) 82 82 168
Best OR ) 273 238 39
SD () 477 50 341
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
Toxicity
Serious AdverseEvents
TemsirolimusBeva(n = 88)
Sunitinib(n = 42)
BevaInterferon(n = 40)
Grade 3 261 119 200
Grade 4 125 24 75
Death 34 0 0
Note 50 of pts in temsirolimusbeva arm ceased therapy before Week 48 for reasons not related to progressive disease primarily toxicity (41)
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Conclusions of the Authors
TORAVA Study Do Not Support Frontline Combination of
Temsirolimus and Bevacizumab in mRCC
Escudier BJ Negrier S Gravis G et al
ASCO 2010 Abstract 4516
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Bevacizumab + Everolimus
Phase II trial of Bevacizumab + Everolimus in pts
with advanced RCC
JD Hainsworthhellip Whorf J Clin Oncol 2010
First an second line therapy
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Bevacizumab + mTOR inhibitor
Bevacizumab + Everolimus phase II study
OutcomesNaiumlve pts
(N = 50)
Pre-treated pts
(N = 30)
OR () 30 23
SD 50 64
N with tumor shrinkage 78 73
PFS (mo) 91 71
Survival (mo) 213 145
Sunitinib or Sorafenib
Hainsworth et al JCO 2010
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Bevacizumab + Everolimus
Bernard Escudier Editorial JCO 2010
bull The final PFS differs 3 and 4 months fewer than in the preliminary report (12 vs 91 for untreated and 11 vs 71 for pre-treated pts)
bull PFS has became the same that of control arm (85-122 months) and less than other standards of care (sunitinib or pazopanib monotherapy -11 months)
bull The rationale for the two large randomized studies is much weaker and questionable
bull Usefulness of phase II non randomized small study
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
How can we overcome the resistance to TKI
Using old and new drugs (IFN hellip)
ldquoRedefining the role of Interferon in the treatment of
malignant diseasesrdquo
Bracarda Eggermont Samuelsson
Eur J Cancer 2010
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As
First- or Second-Line Therapy in mRCC
Gollob et al JCO 2007
bullSorafenib 400 mg orally bid for 8 weeksbullIFN alpha-2b 10 mil IU subcutaneously three times a week
followed by a 2-week break
IL-2 pre-treated pts
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First-
or Second-Line Therapy in mRCC
All pts(40 pts)
First line (20 pts)
Second line (20 pts)
Response n () 13 (33) 10 3
CR 2 (5)
PR 11 (28)
SD 12 (29)
PFS (mo) 10
Dose reduction ( of pts) 65
Gollob et al JCO 2007
Fatigue anorexia anemia diarrhea hypophosphatemia rash nausea and weight loss
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
CARCINOMA RENALE METASTATICO
TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA
STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
Studio GOIM 2901
PIANO DI TRATTAMENTO
bullBraccio A
Everolimus 10 mgdie per via orale
bullBraccio B
Everolimus stesse dosi + Interferone alpha-2a basse dosi sc (3 Mil UI x 3 voltesettimana)
- MECCANISMI DI RESISTENZA AI FARMACI NEL mRCC
- Drugs Resistance in mRCC
- Slide 5
- Drugs Resistance Definition
- Primary and Secondary Resistance
- Pattern of Response to Available Therapy in mRCC
- Drugs Resistence in mRCC Influence of patient risk score and prior therapy
- Percentage of pts who receives a 2d line therapy
- Slide 12
- Resistance to TKI in mRCC
- Resistance Mechanisms in mRCC
- Drugs Resistance Mechanisms
- Primary Resistance to TKI in mRCC
- Primary Resistance
- Slide 18
- Hypoxia the key of the escape
- Angiogenic Escape (II)
- Neoplastic Evolution and Mechanisms of Angiogenic Escape
- PowerPoint Presentation
- Development of Resistance Angiogenic Escape (I)
- Slide 24
- The FGFFGFR pathway is important in patients who develop resistance to sunitinib
- Angiogenic Escape IL-8 mediates resistance to Sunitinib
- High IL-8 levels are associated with resistance to sunitinib
- The epithelial-to-mesenchymal transition process
- Slide 29
- Slide 30
- The epithelial to mesenchymal transition process What significance
- The epithelial to mesenchymal transition process Main characteristics
- The intratumoral heterogeneity and gene mutations
- A specific gene expression signature characterizes metastatic potential in ccRCC
- Slide 35
- Working Model Factors Associated With Resistance
- Factors Associated With Resistance in mRCC
- Slide 38
- Slide 39
- How can we overcome the resistance to TKI
- Slide 46
- Slide 47
- Slide 48
- Adaptive mechanisms of secondary resistance to anti-angiogenic therapies
- Slide 50
- Potential Mechanisms of Treatment Resistance In mRCC
- Slide 52
- Slide 53
- Slide 54
- Everolimus in mRCC (RECORD 1 study)
- Benefit of everolimus after multiple lines of treatment
- mRCC about mTOR inhibition
- Slide 59
- Dofitinib a new multitarget agent
- Slide 61
- Slide 62
- Selected Trials of Second-Line Agents After TKIBeva
- Slide 64
- Estimated PFS of pts receiving sequential therapies
- Optimal Sequence May Depend on Response to First Line Therapy
- Sequential therapy ongoing studies
- Slide 69
- Is Combination Therapy Better
- Combination Drug Therapy Selected Adverse Events
- Slide 72
- Slide 73
- Slide 74
- Slide 75
- EGFR EXPRESSION IN SELECTED HUMAN TUMORS
- Phase III trial of sunitinib plus gefitinib in patients with mRCC (first line)
- Slide 78
- Slide 79
- Slide 80
- Slide 81
- Can the combination of Temsirolimus and Bevacizumab improve the treatment of mRCC Results of the randomized TORAVA phase II trial Escudier BJ Negrier S Gravis G et al ASCO 2010 Abstract 4516
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC RESULTS
- TORAVA Frontline Combination of Temsirolimus and Bevacizumab in mRCC Toxicity
- Conclusions of the Authors TORAVA Study Do Not Support Frontline Combination of Temsirolimus and Bevacizumab in mRCC
- Slide 87
- Slide 88
- Slide 89
- Slide 90
- Slide 91
- Slide 92
- CARCINOMA RENALE METASTATICO TERAPIA DI II LINEA IN PAZIENTI A PROGNOSI FAVOREVOLE-INTERMEDIA STUDIO MULTICENTRICO DI FASE II RANDOMIZZATO
-
