Colorectal Cancer Poster Discussion Discussion of Posters #17 - 25 Wells Messersmith, MD, FACP...
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Transcript of Colorectal Cancer Poster Discussion Discussion of Posters #17 - 25 Wells Messersmith, MD, FACP...
Colorectal Cancer Poster Discussion
Discussion ofPosters #17 - 25Wells Messersmith, MD, FACPDirector, GI Medical OncologyProgram Leader, Developmental TherapeuticsUniversity of Colorado Cancer Center
Learning Objectives
• Describe initial results from clinical trials with novel therapies/strategies in advanced colorectal cancer (CRC)
• Review issues with previously approved agents including panitumumab-induced skin toxicity and management of primary disease in the metastatic setting.
• Insufficient time to discuss every poster.
After reading and reviewing this material, the participant should be better able to:
Novel Therapies: #21, 22• #21 (abstr 3530), Safety Analysis of a
randomized phase II trial of hedgehog pathway inhibitor GDC-0449 (vesmodegib) versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC)
• Authors: Bendell, Hart, Firdaus, Gore, Hermann, Mackey, Graham, Zerivitz, Low, Berlin
• Sponsor: Genentech (NCT00636610)
#21 Signaling Target:
Hedgehog• Developmental pathway; discovered in
drosophila in 1980 in segmentation studies
• Loss-of-function mutations in negative regulator PTCH1 leads to Gorlin Syndrome: basal cell carcinomas (BCC), meduloblastoma, sarcomas.
• Sporadic BCC has high frequency of PTCH1 inactivating mutations, or SMO activating mutations (constitutive activation of HH pathway)
• Crosstalk with Ras, Wnt, Notch, TGF-beta, etc
#21 Signaling Target: HedgehogHedgehog
Stem Cell Maintenance
Patched
(Sonic, Indian, or Desert)
Celium Cell Membrane
Nuclear Membrane
Proliferation and survival
Hedgehog Gene Targets: GLI1, BCL2, SNAIL, etc
Gli
Angiogenesis
Pathway Mechanism:Unknown
InactiveSMO
Activated Gli
SMO
SuFuMutation
Mutation
MutationOverexpression
GDC-0449
Signaling Target:
Hedgehog• Hedgehog inhibitors in development
– GDC-0449 (Vismodegib; Phase I, NEJM1; 33 BCC patients, RR=50-60%; also medulloblastoma patient2)
– IPI-926 (cyclopamine derivative), XL139, LDE225
– Monoclonal antibodies (mAb’s) also being developed
• Role of HH signaling in preclinical models of CRC is complex, involving Wnt pathway crosstalk and paracrine signaling. Possible stem cell effects.
• Little published preclinical data on combinations with conventional chemotherapy / biologics.
1Von Hoff, NEJM 20092Rudin, NEJM 2009
FOLFOX/ or FOLFIRI/B + GDC-0449
• Results: some concerning signals in tox data– More deaths in the GDC-0449 arm (4 vs 0)– Two sudden deaths; two pneumonias (unusual
cause of death for colorectal patients?)– All deaths occurred before the median PFS for
1st line CRC (days 91, 95, 155, 231)– Slightly less exposure to conventional chemo
and biologics in experimental arms
• No PK interactions (preliminary)
• Added toxicities consistent with phase I trial1 1Von Hoff, NEJM 2009
FOLFOX/ or FOLFIRI/B + GDC-0449• What is the future of HH inhibitors in CRC?
– Await efficacy data (median 12 mos f/u only)– Predictive markers may be tricky. In CRC, do not
have mutations (BCC, medulloblastomas), but ligand overexpression occurs in CRC1
– Analysis of archival tissues for biomarkers
• What is the optimal sequence? (i.e., similar to lung CA and oral TKI’s such as erlotinib)
• Re: deaths due to pneumonia, HH can regulate T-cell receptor signaling and immune responses, but this signal was not seen in HHi phase I’s.
1Qualtrough, Int J CA 20042Rowbatham, Cell Cycle 2007
Novel Therapies: #21, 22• #22 (abstr 3531), Final results of a
randomized phase II study of perifosine in combination with capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients with second- or third-line metastatic colorectal cancer (mCRC)
• Authors: Richards, Nemunaitis, Vukelja, Hagenstad, Campos, Letzer, Hermann, Sportelli, Gardner, Bendell
• Sponsor: Keryx/AOI (NCT01048580)Note: Phase III “X-PECT” trial (similar design) launched in April 2010, n=430
Results: capecitabine +/- perifosine• Small trial (n=38; interim analysis, no
power calculation provided but primary endpoint TTP)
• Toxicity profile as expected; perifosine appeared to add fatigue, diarrhea, nausea, anemia. Also surprising rate of g3/4 HFS (30%) in combo arm
• Improvement in– Response rate (4 pts v 1 pt, n=35 total), most
>1 yr(Only one response was in 5-FU refractory)
- Time to progression (28 v. 11 weeks, HR=0.28)- Overall survival (17.7 v 10.9 mos, HR=0.41)
Results: capecitabine +/- perifosine
5-FU REFRACTORY PATIENTS
Median TTP: P-CAP:18 weeks [95% CI (12, 36)]
Median TTP: CAP: 10 weeks [95% CI (6.6, 11)]
p-value = 0.0004
Hazard ratio: 0.186(0.066, 0.521)
ALL EVALUABLE PATIENTS
Median TTP: P-CAP: 28 weeks [95% CI (12, 48)]
Median TTP: CAP: 11 weeks [95% CI (9, 15.9)]
p-value = 0.0012
Hazard ratio: 0.284(0.127, 0.636)
Richards, ASCO 2010
capecitabine +/- perifosine (#22)
What is perifosine? - Oral alkylphospholipid- Related to miltefosine (FDA approved for breast CA cutaneous mets,
and leishmaniasis), which has significant GI side effects- Mechanism of action is complex/unclear. Interacts with cell
membrane and inhibits AKT (indirectly?). Also inhibits NF-ĸB; facilitates degradation of mTOR pathway members; activates JNK (apoptotic) pathway.
Phase I studies- Phase I (daily dosing, 3 on, 1 off) in solid tumors (Eur J Ca 2002)
- n=22, diarrhea and vomiting dose-limiting, MTD 200 mg/day- ½ life 105 hr; 11 CRC patients, no responses
- Phase I (weekly dosing) in solid tumors (Eur J Ca 2010)- n=36, diarrhea/vomiting, RP2D = 600 mg/wk- linear PK, ½-life 80 – 120 hr range, no responses
OP
O
O
O
= N
- according to www.keryx.com, to date >2,000 patients have received perifosine (KRX-0401)
capecitabine +/- perifosine (#22)
Monotherapy studies of perifosine in solid tumors - Phase II study in TKI-resistant renal cell cancer (Cho, ASCO 2009)
- n=24, 100 mg QD, RR=8%, mPFS = 19 wks- Meta-analysis of sarcoma patients in Ph I-II studies (Birch, ASCO
2007)- n= 121, RR = 3%, CBR = 50%; not dose-dependent
- Ph II in HCC (Campos, ASCO 2009)- n= 42, RR = 3%, TTP = 14 wks; daily dose less toxic
- Ph II in 2nd line pancreas cancer (Hedley, ASCO 2005)- n= 19, median TTP = 1.6 mos, mOS = 3.1 mos
Combination studies of perifosine (P) - Phase I of P + sorafenib (Schreeder, ASCO 2008),n=20, 0%RR- Phase II P + imatinib in GIST (Conley, ASCO 2009), n=41, 0% RR- Phase I P + gemcitabine (Wiess, ASCO 2006), 150 mg QD days 1-14- Phase I P + docetaxel (Cervera, ASCO 2006), 150 mg QD days 1-14- Phase I P + radiation (Verheij, ASCO 2004), 150 mg QD
O
Signaling Pathway Target: PI3KLigands
PIP2 PIP3
AKT
mTOR
PI3K
p85
p110
GrowthFactorReceptor
Blocking the Pathway
PI3K inhibitors(XL147, GDC-0941, PX-866, SF1126, BEZ235) AKT inhibitors
(perifosine?, MK-2206 GSK2141795, SR13668, XL418, GSK690693)
mTOR inhibitors(sirolimus, temsirolimus, everolimus, AP23573, AZD8055, OSI-027, palomid 529)
Questions re: perifosine• Multiple lines of evidence suggest PI3K is an
important target in CRC, but mechanism of this drug is unclear.
• No data on biomarkers of activity (e.g., PIK3CA mutants, 15%; loss of PTEN, 20-40%; NF-ĸB levels, etc)
• Little published preclinical data on 5-FU/perifosine– NF-ĸB rationale is based on plasma cell paper in Blood
• Is capecitabine standard after failure of FOLFOX, FOLFIRI, and EGFR mAb (KRAS WT)?
• Optimal dose/schedule somewhat unclear. This study used <25% of daily tolerated monotherapy dose.
• Are we getting too excited about the interim analysis of a small study?
Novel Strategies: #23, 24, 25• #24 (abstr 3533), DUX Study: a phase II
study of evaluating dual targeting of the EGFR using the combination of cetuximab and erlotinib in patients with chemotherapy refractory metastatic colorectal cancer
• Authors: Weickhardt, Price, Pavlakis, Skrinos, Dobrovic, Salemi, Scott, Mariadason, Chong, Tebbutt
• Sponsor: Austin Health (NCT00784667)
Dual Inhibition of EGFR (mAb, TKI)• Recall that there has been fairly extensive experience with EGFR TKI’s erlotinib and gefitinib in CRC, with evidence of activity in combos.
Monotherapy studies (few responses; short PFS)
• ~30% SD rate for erlotinib (Townsley, Br J CA 2006)
• ~30% SD for gefitinib (Mackenzie, IND 2005)
Gefitinib Combination Studies (active)• FOLFOX/gefit (Fisher, CCR 2008) RR=72%,
TTP= 9.3m
• FOLFOX/gefit (Zampino, Cancer 2007) RR=74%
• CAPOX/gefit (Gelibter, Cur Med Res Opin 2007)
RR=49%
Dual Inhibition of EGFR (mAb, TKI)• Experience with EGFR TKI’s erlotinib and gefitinib
Erlotinib Combination Studies (active)• XELOX/erlot (Meyerhardt, JCO 2006)
– RR=25% 2nd line
• XELOX/erlot (Van Cutsem, Ann Onc 2007)
– RR=33% 2nd line
• FOLFOX/Bev/erlot (Mayerhardt, Ann Onc 2007)– RR=34% 2nd line
• FOLFOX/Bev/erlot (Messersmith, accepted 2010)– RR=78%, OS=30m
Dual Inhibition of EGFR (mAb, TKI)• However, toxicity has been considerable
Gefitinib StudiesFOLFOX/gefit (Kuo, JCO 2005)
G3/4 toxicities: 48% diarrhea, 48% neutropenia, 22% n/v
FOLFOX/gefit (Fisher, CCR 2008) G3/4 toxicities: 67% diarrhea, 60% neutropenia and g2 rash
Erlotinib StudiesXELOX/erlot (Meyerhardt, JCO 2006)
G3/4 toxicities: 38% diarrhea, 19% nausea/vomiting, 16% fatigue
FOLFOX/Bev/erlot (Mayerhardt, Ann Oncol 2007) Nearly all 35 patients discontinued due to toxicity
FOLFIRI/erlot (Messersmith, Clin Can Res 2004) Halted after 6 patients due to toxicity (mainly rash)
“DREAM” studyHalted/amended after safety analysis
Double-Targeting EGFR
Tyrosine Kinase Inhibitor
Compensatory overexpressionof EGFR?
EGFR
MonoclonalAntibody
Endocytosisof EGFR
EGFR
Dual Inhibition of EGFR (mAb, TKI)
Published phase I study of cetuximab / erlotinib1
• Erlotinib fixed at 150 mg daily• Cetuximab escalated weekly without loading
dose starting at 100 mg/m2 (200, 250)• N=22 (14 NSCLC)• One DLT of g3 skin rash; 100% had rash g1-
3• Full doses (250 C and 150 E) achieved• 39% had SD lasting median 16 weeks
1Guarino, Oncologist 2009
Dual Inhibition of EGFR (mAb, TKI)
Results of “DUX” study• N=50, 22% KRAS, 16% BRAF, 8% PIK3CA MT• All previously treated with oxaliplatin,
irinotecan• 15 of 29 (52%) KRAS/BRAF WT patients
responded (0/11 KRAS MT, 0/8 BRAF MT)• In KRAS/BRAF WT group, mPFS = 5.6 mos,
mOS = 14 mos (2.7 and 7.3 mos for KRAS MT)
• Toxicities were significant: 46% grade 3 / 4 rash, 40% grade 3 / 4 hypomagnesemia
• Would patients value this trade-off?
Dual Inhibition of EGFR (mAb, TKI)
Another study of “double targeting” (asking question of the addition of irintecan)
- Erlotinib and Panitumumab With or Without Irinotecan as 2nd-Line Therapy in Patients With Metastatic CRC– (PI: Al B. Benson, Northwestern) – 2nd line, n=96– ClinicalTrials.gov ID: NCT00940316(Recently opened, accrual ongoing)
Novel Strategies: #23, 24, 25• #25(abstr 3235), Phase II trial of
bevacizumab plus everolimus (mTOR inhibitor) for refractory metastatic colorectal cancer
• Authors: Altomare, Russell, Uronis, Morse, Hsu, Zafar, Bendell, Starodub, Honeycutt, Hurwitz
• Sponsor: Duke (NCT00597506)
Note: there are studies of this combination in renal cell (JCO 2010), neuroendocrine, meningioma, ovarian, prostate, HCC, and melanoma.
bevacizumab / everolimus:
#25• Expanded cohort (n=50) using
– Bev 10 mg/kg q2 weeks, Everolimus 10 mg daily
• Toxicity– 14% g3/4 HTN; 6% g3/4 mucositis,
fistula/abcess– 68% grade 1-2 mucositis– 62% patients held drug for everolimus toxicity
• Efficacy (n=48)– No PR’s, PFS = 2.28 mos, median OS = 7.87
mos
Difficult to see a bright future ahead for this combination in this setting; other combo’s pending.
Novel Strategies: #23, 24, 25• #23 (abstr 3532), A randomized, phase IIB
study of sunitinib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 as first-line treatment for mCRC: interim results
• Authors: Hecht, Yoshino, Mitchell, Dees, Countouriotis, Maneval, Kretzschmar
• Sponsor: Pfizer (NCT00609622)
FOLFOX/Sunitinib vs bev:
#23
Higher toxicity, lower doseintensity of FOLFOX, HR =
1.6
Sunitinib (SU) + mFOLFOX6Median: 9.1 months (95% CI: 7.5–9.4)
Bevacizumab (BEV) + mFOLFOX6Median: 11.2 months (95% CI: 9.1–15.6)
HR =1.598 (95% CI: 0.942 2.712)p = 0.96*
Progression-Free Survival
1.0
0.8
0.6
0.4
0.2
0
Pro
gre
ssio
n-f
ree
surv
ival
pro
bab
ilit
y
0 2 4 6 8 10 12 14 16 18Time (months)
Patients at riskSU+ mFOLFOX6 96 86 71 53 45 37 20 9 6 2 0 0 0BEV + mFOLFOX6 95 86 73 55 48 34 21 14 12 4 2 1 0
*p-value from 1-sided stratified log-rank test for superiority
VEGFR TKI’s in CRC: no success yet
Agent a.k.a mCRC Trials CRC Patients
Cediranib AZD2171 2 Phase III 3,194
Semaxinib SU5416 2 Phase III 2,084
Vatalanib PTK787 2 Phase III 2,050
Sunitinib SU11248 Phase III 1,623
Brivanib BMS-582664 Phase III 926
Regorafenib BAY 73-4506 Phase III 730
Sorafenib BAY 43-9006 Phase IIB 814
Vandetanib ZD6474 Phase IIB 356
Axitinib AG-013736 Phase IIB 299
Linifanib ABT-869 Phase IIB 147
Vargateg BIBF 1120 Phase II 166
Tivozanib AV-951 Phase II 80
Motesanib AMG-706 Phase IB 148
Pazopanib GW786034 Phase IB 94>10,000Courtesy of Scott Kopetz
Management of Primary: #19• #19 (abstr 3527), A phase II trial of
mFOLFOX6 chemotherapy plus bev for patients with unresectable stage IV colon cancer and synchronous asymptomatic primary tumor: results of NSABP C-10
• Authors: McCahill, Yothers, Sharif, Petrelli, Lopa, O’Connell, Wolmark
• Sponsor: NSABP (NCT00321828)
Management of Primary: #19• The question is important for clinical
practice• Most data to this point was retrospective
• Study population: Stage IV unresectable with intact primary; no bleeding, obstruction
• Primary endpoint: event rate related to intact primary tumor requiring surgery (bleeding, perforation, obstruction); or death from 1°
• Results: n=86, 12% required surgery, 2 died (1 perforation, 1 obstruction); mOS 20 mos.
• Supports leaving 1° in stage IV unresectable CRC (small study)
Side Effects: #19/20• #19 (abstr 3528) FOLFOX4+/- Panitumumab
first-line treatment for metastatic CRC: Efficacy by skin toxicity (from “PRIME” study)
Authors: Douillard, Cassidy, Jassem, Rivera, Kocakova, Rogowski, Canon, Yanez, Xu, Gansert
• #20 (abstr 3529) FOLFIRI +/- Pmab second-line (“181”) Efficacy by skin toxicity
Authors: Price, Sobrero, Wilson, Van Cutsem, Aleknaviciene, Zaniboni, Hartmann, Tian, Gansert, Peeters
• Sponsor: AmgenNote: Clinical trial results presented at ESMO 2009, ASCO GI 2010
Rash and “PRIME” Study:
#19
ASCO 2010
OS by Worst Grade ST Severity*
*OS analyses by worst ST included all patients treated with panitumumab with a PFS of at least 28 days
NE = Not evaluable
Association between ST severity and OS: HR (Gr 2 - 4 : 0 - 1) = 0.595 (95% CI: 0.417 - 0.849), p = 0.0042
Su
rviv
alP
rob
abili
ty
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Su
rviv
alP
rob
abili
ty
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Association between ST severity and OS: HR (Gr 2 - 4 : 0 - 1) = 0.455 (95% CI: 0.318 - 0.651), p < 0.0001
Eventsn (%)
Median months
Grade 2-4 114 / 250 (46) 28.3 (23.9 – NE)
Grade 0-1 44 / 64 (69) 11.5 (9.1 – 20.2)
Eventsn (%)
Median months
Grade 2-4 98 / 146 (67) 17.0 (14.9 – 20.2)
Grade 0-1 50 / 63 (79) 10.1 (7.2 – 13.3)
WT KRAS MT KRAS
Note: MT KRAS group with g2-4 rash did better than WT KRAS g0-1
11.5 mos 17 mos
Rash and EGFR-targeting agents
In this phase II trial of erlotinib in patients with refractory NSCLC, subjects with rash lived longer (overall RR= 12%).
No differences based on EGFR staining. EGFR mutational status unknown.
Perez-Solar, JCO 2004
Rash and EGFR: consistent results
Perez-Solar and Saltz, JCO 2005
The Enigma of Rash and Outcome
Dose
Rash
Outcome
PK
Germline explanation1: Modulation of EGFR gene transcription by a polymorphic dinucleotide repeat in intron 1
(Lower number of repeats = higher expression EGFR)
1Gebhardt, JBC 1999; 2Rudin, JCO 2008
Courtesy ofManuel Hidalgo
PK/PD Study of Erlotinib (n=80)Variability in skin rash best explained by a multivariate logistic regression model incorporating erlotinib PK trough (P = .034) and EGFR intron 1 polymorphism (P = .044). 2
Conclusions• Finally we are seeing new agents in CRC.
– Perifosine trial very small, but promising– If perifosine phase III trial is positive, we will be
left guessing the mechanism (& thus potential biomakers)
– Vismodegib (HH) efficacy results awaited
• Dual targeting EGFR with mAb and TKI has activity in KRAS WT CRC, but with toxicity trade off (rash and hypoMg)
• In metastatic unresectable setting, asymptomatic primary disease can be left alone.
• Issue of EGFR mAb’s and rash remains unclear.
Colorectal Cancer Poster Discussion
Thank you (and safe flight)!Wells Messersmith, MD, [email protected], GI Medical OncologyProgram Leader, Developmental TherapeuticsUniversity of Colorado Cancer Center