Roberto Sabbatini Azienda Ospedaliero Universitaria di Modena Policlicnico di Modena HOT TOPICS...
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Roberto SabbatiniAzienda Ospedaliero Universitaria di Modena
Policlicnico di Modena
HOT TOPICSHOT TOPICSControversie OncologicheControversie Oncologiche
Prima linea di TrattamentoPrima linea di Trattamento
Scuola di UrOncologiaTumore del rene
Roma 23-24 maggio 2014
My disclosuresMy disclosures
• RCC accounts for:– 80–85% of renal cancers1 – 2–3% of all adult malignancies2
– 63,000 new cases/year in Europe
– 26,000 mortalities annually
• RCC is: – More common in men than
women3,4
– Most frequently occurs in 60–70 year olds4
– More common in people from Northern European and North American countries3,4
1. Motzer RJ et al. N Engl J Med 1996;335:865–75; 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559; 3. GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/; 4. Cancer Research UK, UK kidney cancer statistics. 2008 http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441.
Incidence
Mortality
Renal Cell CarcinomaThe epidemiology
Renal Cell CarcinomaThe epidemiology
Renal Cell Carcinoma: an unrelenting, progressive disease
Renal Cell Carcinoma: an unrelenting, progressive disease
Presentation at diagnosis1:45% with localized disease
25% with locally advanced disease
20–30% metastatic disease
33% of patients treated for localized disease will develop metastatic disease2
Common sites of metastasis include lung (75%), liver (18%), bone (20%), brain (8%)3
Median survival for patients with metastatic RCC in the era of cytokine was 6–12 months4–7
1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90 . 3. Sachdeva K et al. Renal cell carcinoma., in eMedicine. 2008; 4. Gay PC et al. J Neurooncol 1987;5:51–6; 5. Decker DA et al. J Clin Oncol 1984;2:169–73; 6. Culine S et al. Cancer 1998;83:2548–53; 7. Doh LS et al. Oncology 2006;20:603–13.
Disease specific survival by Time Period ofnon-Clear Cell RCC pts
Disease specific survival by Time Period ofClear Cell RCC pts
Disease-Specific Survival in de novo mRCC in the Cytokine and Targeted Therapy Era
Pal SK, PLoS ONE 2013
AxitinibAxitinib
Cytokine/Cytokine/Sunitinib failureSunitinib failure
2005 2006 20072005 2006 2007 2008 2008 2009 2009
Explosion of Targeted Therapy forExplosion of Targeted Therapy for mRCC (phase III trial) mRCC (phase III trial)
2006 20072006 2007 2008 2008 2009 2010 2009 2010 20142014
EverolimusEverolimus
VEGFi-failureVEGFi-failure
PazopanibPazopanib
I line and I line and cytokine-failure cytokine-failure
Key drivers in first-line treatment selection: Key drivers in first-line treatment selection: Efficacy and ExperienceEfficacy and Experience
Clinical efficacy = primary driver to guide treatment
decisions
Targeted agents: Standard of care for mRCC
Schmidinger M, Kidney Cancer Symposium, Vienna 2012
Temsirolimus (Hudes 2007)
Sorafenib (Escudier , 2007)
Bev + INF-α (Rini, 2008)
Bev + INF-α (Escudier 2007)
Sunitinib (Motzer 2007)
Pazopanib (Sternberg 2010)
Target
CALGB 90206
AVOREN
A6181034
VEG105192
3.7/5.5
5.7*
8.5*
10.2*
11.0*
11.1*
1.9
3 (Placebo)
5.4 (IFN)
5.2 (IFN)
5.1 (IFN)
2.8 (Placebo)
11 10 8 5 0
Sperimental Arm Control Arm*p<.05
4 8 mos
Ist-line phase III trials in mRCCIst-line phase III trials in mRCCProgression Free SurvivalProgression Free Survival
7–97–9Kane 2006Kane 2006
7.37.3IFNIFN10.9*10.9*TemsirolimusTemsirolimus
15.215.2PlaceboPlacebo17.817.8SorafenibSorafenib
17.417.4IFN Rini ASCO 2009IFN Rini ASCO 200918.318.3BEV/IFNBEV/IFN
18.518.5Gore ASCO 2008Gore ASCO 200818.718.7
19.819.8IFNIFNNRNR
22.922.9
Bevacizumab + IFNBevacizumab + IFN
20.520.5Sternberg EJC 2010Sternberg EJC 2010
21.821.8
PlaceboPlacebo
26.426.4IFNIFN
2007 to2007 to
presentpresent
Phase III trials in mRCCPhase III trials in mRCCOverall SurvivalOverall Survival
*p<.05
Motzer JCO 2009Motzer JCO 2009
SunitinibSunitinibMotzer 2013Motzer 2013
29.329.328.428.4
SettingSetting TherapyTherapyLevel 1Level 1 Level 2Level 2
First-line
Therapy
Low+Intermed
Risk
Sunitinib
Beva/IFN
Pazopanib
HD Il-2
Sorafenib
Poor
Risk
Temsirolimus Sunitinib
Clinical trial
Second-line
Therapy
Prior
Cytokine
Sorafenib
Pazopanib
Axitinib
Sunitinib
Clinical trial
Prior TKi Everolimus
Axitinib
Sequential TKi
Algorithm for Clear Cell RCC 2012Algorithm for Clear Cell RCC 2012
2nd-generation trials: Head to Head studies 1st-line phase III trial in mRCC
Agents N. pts Line of
treatment
Median PFS
(mos)
Median OS
(mos)
Tivozanib vs Sorafenib1 500
First or
CK treated11.9 vs 9.1* NA
Everolimus–Sunitinib vs
Sunitinib-Everolimus2
471 First 7.8 vs 10.7* NA
Axitinib vs
Sorafenib288 First 10.1 vs 6.5* NA
Pazopanib vs Sunitinib4 1110 First 8.4 vs 9.5 28.4 vs 29.3
Axitinib
“dose tritation”5213 First
16.6 (not eligible) vs
14.5 (eligible)
NA
* p< .051. Motzer R, ASCO 2012; 2. Motzer R. ASCO 2013; 3. Hudson TE, ASCO-GU 20134. Motzer R, NEJM 2013; 5. Rini B, ASCO-GU 2013
Case study: TIVO-1Treatment allocation imbalance?
Motzer RJ, et al. J Clin Oncol 2013
Sorafenib 400 mg BID (n=257)
• Recurrent or mRCC with a clear cell component
• Measurable disease
• Treatment-naïve or 1 prior treatment: cytokines, investigational agent, hormonal therapy, chemotherapy
• Prior nephrectomy
• ECOG PS 0 or 1
n=5171:1
Tivozanib 1.5 mg/day (3 weeks on-treatment;
1 week off-treatment) (n=260)
RANDOMISATION
Cross-over with Tivozanib 1.5 mg/day permitted upon disease progression;
extension protocol (NCT01076010)
Phase III randomized, open label multicenter trial:•Primary endpoint: PFS by independent review (assessment of response every 8 wks)•Secondary endpoints: overall survival, ORR, quality of life
Primary endpoint: Tivozanib significantly prolonged PFS versus sunitinib
Overall population
n Median PFS (95% CI) HR P
value
Tivozanib 260 11.9 mos (9.3–
14.7) 0.797 0.042
Sorafenib 257 9.1 mos (7.3–
9.5)
PF
S p
roba
bilit
y
Time, months0 5 10 15 20
1.0
0.8
0.6
0.4
0.2
0.0
Motzer RJ, et al. J Clin Oncol 2013
BUT - No significant difference in OS (secondary endpoint)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
0
20
40
60
80
100
Time (months)
% s
urv
iva
l
Motzer RJ, et al. J Clin Oncol 2013FDA. Tivozanib, June 2013.
n Median OS (95% CI) HR P
value
Tivozanib 260 28.8 mos (22.5–
NR)1.25 0.105
Sorafenib 257 29.3 mos (29.3–
NR)
Overall population
Why no OS benefit?
1. Garnick MB. J Clin Oncol 20132. FDA. Tivozanib, June 2013. http://www.fda.gov
• A sequential trial of two agents, sorafenib followed by tivozanib, compared with one agent, tivozanib
• “The sanctity of OS was compromised”1
Sorafenib 400 mg BID
(n=257)
Tivozanib 1.5 mg/day (3 weeks on-treatment; 1 week off-treatment)
(n=260)
RANDOMISATION
*Due to lack of available TKIs in Eastern Europe
Balanced?
Infrequent second line treatment at time of
disease progression*
Infrequent second line treatment at time of
disease progression*
Cross over to tivozanib at time of
disease progression
Cross over to tivozanib at time of
disease progression
FDA conclusion: “Inconsistent PFS and OS results and imbalance in post-study treatments make the trial results inconclusive when making a risk-benefit assessment necessary for approval.”2
At the time of the final OS
analysis, 156 patients (61%)
randomly assigned to sorafenib
had crossed over to tivozanib
Sunitinib50 mg qd
4 wk on/2 wk off
Sunitinib50 mg qd
4 wk on/2 wk off
Pazopanib800 mg qd
Continuous dosing
COMPARZ: a non-inferiority trial
• Stratification factors:
• Karnofksy Performance Status (KPS; 70/80 vs. 90/100)
• Prior nephrectomy (yes vs. no)
• Baseline lactate dehydrogenase (LDH; >1.5 vs. ≤1.5 x ULN)
Randomized 1:1
(N = 1110)
NCT01147822, n = 183
NCT00720941, n = 927
Motzer R, NEJM 2013
Primary Endpoint: PFS (Independent Review)
17
Median PFS (95% CI)
Pazopanib 8.4 mo (8.3, 10.9)
Sunitinib 9.5 mo (8.3, 11.1)
HR (95% CI ) = 1.047 (0.898,1.220)
Motzer R, NEJM 2013
18
Chemistry labs
Pazopanib (n = 554) % Sunitinib (n = 548) %
All Grades Grade 3/4 All Grades Grade 3/4
AST 61 11/1 60 3/0ALT 60 15/2 43 4/<1Hyperglycemia 54 5/0 57 4/<1Total bilirubin 36 3/<1 27 2/<1Hypophosphatemia 36 4/0 52 8/<1Hyponatremia 35 7/<1 32 7/<1Hypoalbuminemia 33 <1/0 42 2/0Creatinine 32 <1/0 46 <1/<1
Hematology labs
Leukopenia 43 1/0 78 6/0
Neutropenia 37 4/<1 68 19/1
Thrombocytopenia 41 3/<1 78 18/4
Lymphopenia 38 5/0 55 14/<1
Anemia 31 1/<1 60 6/1a Reported in (≥30%) of patients in either arm.Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib.Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib.
Laboratory Abnormalitiesa
Motzer R, NEJM 2013
19
Adverse Eventa
Pazopanib (n = 554) % Sunitinib (n = 548) %
All Grades Grade 3/4 All Grades Grade 3/4
Any eventb >99 59/15 >99 57/17
Diarrhea 63 9/0 57 7/<1
Fatigue 55 10/<1 63 17/<1
Hypertension 46 15/<1 41 15/<1
Nausea 45 2/0 46 2/0
Decreased appetite 37 1/0 37 3/0
Hair color changes 30 0/0 10 <1/0
Hand-foot syndrome 29 6/0 50 11/<1
Common Treatment-Emergent Adverse Eventsa
a Adverse events ≥30% in either armb 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.Rows highlighted in yellow indicate events for which relative risk of occurrence is higher with pazopanib.Rows highlighted in blue indicate events for which relative risk of occurrence is higher with sunitinib.
Motzer R, NEJM 2013
……. The median duration of treatment was similar in the two groups: 8.0 months (range, 0 to 40) in the pazopanib group and 7.6 months (range, 0 to 38) in the sunitinib group. Similar percentages of patients in the pazopanib and sunitinib groups had a dose interruption of 7 days or more (44% and 49%, respectively) or a reduction in the dose (44% and 51%, respectively). The proportion of patients who discontinued the study drug because of adverse events was 24% in the pazopanib group and20% in the sunitinib group (Table S5 in the Supplementary Appendix); the higher discontinuationrate observed for pazopanib, as compared with sunitinib, was primarily due to abnormalities in liver-function tests (6% vs. 1%).
COMPARZ trial: Adverse Events
Motzer R, NEJM 2013
….. There were no between-group differences inthe rates of cardiovascular adverse events. Thepercentages of patients meeting cardiac-dysfunctioncriteria15 were similar: 13% in the pazopanib group and 11% in the sunitinib group (Table S7 in the Supplementary Appendix). The incidence of myocardial infarction or ischemia was similar in the pazopanib and sunitinib groups (2% and 4%, respectively).
EverolimusEverolimus10 mg/day 10 mg/day
Sunitinib50 mg/day***
2nd Line*NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.
Primary
• PFS-1st line
Secondary
• Combined PFS
• ORR-1st line
• OS
• Safety
Study Study endpointsendpoints
1 : 1
RRAANNDDOOMMIIZZ
E**E**
EverolimusEverolimus10 mg/day 10 mg/day
SSCCRREEEENN Sunitinib
50 mg/day***
1st Line
RECORD-3: Phase II randomized trial comparing sequential 1st-line everolimus and 2nd-line sunitinib vs 1st-line sunitinib
and 2nd-line everolimus
Motzer R, ECC 2013
Primary Endpoint: 1st-line PFS for non-inferiority of everolimus vs sunitinib
• Bayesian method: non-inferiority declared if observed HR ≤1.1 (1-month difference in the median first-line PFS)
• 318 first-line events needed (total 460 patients)
Primary End Point: First-line PFS100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
Time (months)
238233
164181
118145
88108
6884
4455
3142
2328
1215
59
03
00
Number of patients still at riskEverolimusSunitinib
Everolimus (events/N = 182/238)
Sunitinib (events/N = 158/233)Cum
ulat
ive
even
t-fr
ee p
roba
bilit
y (%
)
K-M Median PFS (mo)
Everolimus Sunitinib
7.85 10.71
Hazard Ratio = 1.43Two-sided 95% CI [1.15, 1.77]
Motzer R, ECC 2013
RECORD-3: combined PFS*
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33
EVE→SUNSUN→EVE
238
Number of patients still at risk
233186196
145171
112135
88105
6574
4852
3735
1919
612
04
00
Cum
ulat
ive
even
t-fr
ee p
roba
bilit
y (%
)
Time (months)
EVE→SUN (events/N = 88/238)
SUN→EVE (events/N = 80/233)
*Time from randomization to progression following second-line treatment or death (any time).
K-M Median PFS (mo)
EVE→SUN SUN→EVE
21.13 25.79
Hazard Ratio = 1.28Two-sided 95% CI [0.94, 1.73]
Log-rank p-value = 0.116
Motzer R, ECC 2013
RECOR-3: Overall Survival100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Cum
ulat
ive
even
t-fr
ee p
roba
bilit
y (%
)
Time (months)
EVE→SUN (events/N = 108/238)
SUN→EVE (events/N = 96/233)
238Number of patients still at risk
233208220
189198
165185
151164
137152
103115
6671
4338
1522
26
01
00
K-M Median OS (mo)
EVE→SUN SUN→EVE
22.41 32.03
Hazard Ratio = 1.24Two-sided 95% CI [0.94, 1.64]
EVE→SUNSUN→EVE
• Drugs blinded by over-encapsulation
• Patients on sunitinib received matchingplacebo during 2-week ‘off-period’
2-week washout Period 2Period 1 Off study
1:1 Randomisation
Patient choiceof treatment
to progressionn=169
Sunitinib50 mg 4/2,10 weeks
Sunitinib50 mg 4/2,10 weeks
Pazopanib800 mg once
daily, 10 weeks
Pazopanib800 mg once
daily, 10 weeks
Sunitinib50 mg 4/2,10 weeks
Sunitinib50 mg 4/2,10 weeks
Time (weeks)0 12 2210
Double-blind
PISCESTiming assessments
Escudier B, et al. JCO 2014
Cross-over design:
Primary endpoint:Significantly more pts preferred PAZO over SUNI
Pat
ient
s, %
p<0.001
70%(n=80)
22%(n=25)
8%(n=9)
Patients were still blinded when they stated their preference
Escudier B, et al. JCO 2014
Temsirolimus (Hudes 2007)
Sorafenib (Escudier , 2007)
Bev + INF-α (Rini, 2008)
Bev + INF-α (Escudier 2007)
Sunitinib (Motzer 2007)
Pazopanib (Sternberg 2010)
Target
CALGB 90206
AVOREN
A6181034
VEG105192
3.7/5.5
5.7*
8.5*
10.2*
11.0*
11.1*
1.9
3 (Placebo)
5.4 (IFN)
5.2 (IFN)
5.1 (IFN)
2.8 (Placebo)
11 10 8 5 0
Sperimental Arm Control Arm
Tivozanib (Motzer 2013) VEG10519211.9* 9.1 (Sorafenib)
COMPARZ8.4 9.5 (Sunitinib)Pazopanib (Motzer 2013)
*p<.05 4 8 mos
Ist-line phase III trials in mRCCIst-line phase III trials in mRCCProgression Free SurvivalProgression Free Survival
RECORD-3Everolimus (Motzer 2014) 7.8 10.7 (Sunitinib)
SettingSetting TherapyTherapyLevel 1Level 1 Level 2Level 2
First-line
Therapy
Low+Intermed
Risk
Sunitinib
Beva/IFN
Pazopanib
HD Il-2
Sorafenib
Poor
Risk
Temsirolimus Sunitinib
Clinical trial
Second-line
Therapy
Prior
Cytokine
Sorafenib
Pazopanib
Axitinib
Sunitinib
Clinical trial
Prior TKi Everolimus
Axitinib
Sequential TKi
Algorithm for Clear Cell RCC 2014Algorithm for Clear Cell RCC 2014
Key drivers in first-line treatment selection: Key drivers in first-line treatment selection: Efficacy and ExperienceEfficacy and Experience
Clinical efficacy = primary driver to guide treatment
decisions
Safety and Clinical experience should also be considered when making treatment
decisions
Targeted agents: Standard of care for mRCC
Schmidinger M, Kidney Cancer Symposium, Vienna 2012
EBGuideline
Efficacy
Safety
Multiple factors that should be considered when Multiple factors that should be considered when selecting a targeted therapy for mRCC ptsselecting a targeted therapy for mRCC pts
PatientProflie
Safety
Major drugs suspected of potential drug interaction with targeted agents
EBGuideline
Efficacy
Safety
Multiple factors that should be considered Multiple factors that should be considered when selecting a targeted therapy for mRCC ptswhen selecting a targeted therapy for mRCC pts
PatientProflie
Patient Profile
Safety
Tolerability Profiles Can Help to Guide Tolerability Profiles Can Help to Guide Selection of Treatment: Selection of Treatment:
Patient-related Factors and Comorbidities Patient-related Factors and Comorbidities
Patient with reduced EF Patient with reduced EF Patients with impaired Patients with impaired mobilitymobility
Patient with nutrition Patient with nutrition disordersdisorders
Consider the Consider the patientpatient''s professions profession
ConsiderConsidercomedicationscomedications
(drug interactions)(drug interactions)33
Chronic obstructiveChronic obstructivepulmonary diseasepulmonary disease
Thromboembolic diseaseThromboembolic disease Diabetes MellitusDiabetes Mellitus
clinical trial populations may not clinical trial populations may not
represent real-life populations of represent real-life populations of
patients, because trial inclusion patients, because trial inclusion
and exclusion criteria often and exclusion criteria often
eliminate numerous patients eliminate numerous patients
from studyfrom study
Targeted Therapies Real WorldTargeted Therapies Real World
EBGuideline
Efficacy
Safety
Multiple factors that should be considered when selecting Multiple factors that should be considered when selecting a targeted therapy for mRCC ptsa targeted therapy for mRCC pts
PatientProflie
Patient Profile
ClinicianFamiliarity
Safety
Ist-line Targeted Therapy: rates of treatment Ist-line Targeted Therapy: rates of treatment interruptions, reductions and discontinuationsinterruptions, reductions and discontinuations
% of pts% of pts SUNISUNI11
n. n. 375375
BEVABEVA22
plus IFNplus IFNn. 337n. 337
PAZOPAZO33
n. 290n. 290TIVOTIVO55
n. 259n. 259TEMTEM44
n. 208n. 208SORASORA66
n. 451n. 451
Dose reductionDose reduction 32 40 24 12 23 13
Treatment Treatment interruptioninterruption
38 NA NA 18 NA 21
*Treatment *Treatment discontinuationdiscontinuation
8 28 14 4 7 10
* No lack of efficacy
SUNISUNI77
EAPEAPn. 1381n. 1381
43
NA
14
SORASORA88
ARCCSARCCSn.2504n.2504
35
50
10
1. Motzer, et al. JCO 2009; 2.1. Motzer, et al. JCO 2009; 2. Escudier, et al. Lancet 2007; 3. Escudier, et al. Lancet 2007; 3. Sternberg, et al JCO 2010 Sternberg, et al JCO 2010 4. Hudes, et al. NEJM 2007;4. Hudes, et al. NEJM 2007; 5. Motzer, et al . ASCO 2012; 6. Escudier et al. NEJM 2007 5. Motzer, et al . ASCO 2012; 6. Escudier et al. NEJM 20077. Gore et al. Lancet 2009; 8. Stadler et al, Cancer 20107. Gore et al. Lancet 2009; 8. Stadler et al, Cancer 2010
Tar
get
ed A
gen
t
Man
agem
ent
AE
s
Healthcare Resources and Increased CostsHealthcare Resources and Increased Costs
EBGuideline
Efficacy
Safety
Multiple factors that should be considered whenMultiple factors that should be considered when selecting a targeted therapy for mRCC ptsselecting a targeted therapy for mRCC pts
PatientProflie
Patient-ReportedOutcomes
Patient Profile
ClinicianFamiliarity
Safety
39
Which targeted agent do you use in 1st-line mRCC: some answers more questions
mRCC treatment: to personalize or not to personalize?
Patients Preferences: going forward by going backward?
Patient-reported Outcomes: what can we do?
Hot Question in mRCC