Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528

Gastrointestinal Colorectal CancerPoster DiscussionSession#3523 - #3528 Josep Tabernero, MD Vall d’Hebron University Hospital Barcelona, Spain

Disclosure • Consutant or Advisory Role: • Amgen • Biogen Idec • Bristol-Myers Squibb • Merck-SeronoKGaA • Novartis • Onyx • Pfizer • Roche • Sanofi-Aventis

Outline • New therapeutic options in mCRC: • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al • Maintenance treatment in mCRC: • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al • Predictive/prognostic biomarkers in mCRC: • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

PICCOLO: initial trial design (Dec 2006) target n = 1125 (494 accrued by end of May 2008) confirmed aCRC, measurable disease progression during/after prior FP ± oxali no prior irinotecan WHO PS 0-2 IrCs irinotecan + ciclosporin Ir irinotecan alone IrPan irinotecan + panitumumab Irvs IrCs non-inferior efficacy primary endpoint PFS at 12 wks Irvs IrPan superior efficacy primary endpoint OS

PICCOLO: amendment from June 2008 target total n = 1200 (including 494 accrued under previous design) eligibility as before KRAS mutated or unknown KRAS-wt (c.12/13 & 61) IrCs irinotecan + c’sporin IrPan irinotecan + pan’mab Ir irinotecan alone Ir irinotecan alone Irvs IrCs non-inferior efficacy primary endpoint PFS at 12 wks Irvs IrPan superior efficacy primary endpoint OS

PICCOLO: Ir vs. IrPan – Analysis populations Primary analysis population (red circle, n=460): KRAS12-13,61-wt, unpretreated “Double wild-type” (n=384): confirmed to also be BRAF-wt “All wild-type” (n=265): wt at KRAS12-13,61 KRAS146 NRAS12-13,61and BRAF

PICCOLO: Ir vs. IrPan – Efficacy analysis Statistics: Ir versus IrPan: • Superiority on OS, primary analysis KRAS-wt, no prior anti-EGFR • 80% power, 2-sided 5% significance, HR = 0.7, mOS 9  12.7 m, 246 events Response rate: • Response rate: 12% vs 34%; p < 0.0001 • Disease Control rate: 51% vs 59%; p = 0.10 Progression-free Survival; KRAS-wt Overall Survival; KRAS-wt HR=0.78 [0.64, 0.95], p=0.01 460 patients, 399 events mPFS: 4.7 mo (Ir), 5.5 mo (IrPan) HR=0.91 [0.73, 1.14], p=0.44 460 patients, 312 events mOS: 10.5 mo (Ir), 10.4 mo (IrPan) Ir IrPan Ir IrPan

PICCOLO: Clinical implications – 2nd line mCRC D Morton, et al. for the FOxTROT Collaborative Group. ASCO 2011, Abstract #3568 A Sobrero et al. EPIC study, J ClinOncol 2008; 26:2311-2319; M Peeters et al. J CinOncol 2010; 28:4706-4713

SOX vs COX in mCRC: Study design S-1 80 mg/m2 days 1-14 Oxaliplatin 130 mg/m2 day 1 q3w Primary Site Prior Adjuvant Treatment Measurable or Evaluable Disease • Primary objective: • PFS • Secondary objectives: • OS • ORR • QoL • Safety A Stratification Randomization Capecitabine 2000 mg/m2 days 1-14 Oxaliplatin 130 mg/m2 day 1 q3w B 344 Pts., 11 Centers 12 months enrollment, 12 moths F/U

SOX vs COX in mCRC: Statistical hypothesis • Non-inferiority study: SOX is non-inferior to COX in PFS • The upper limit of 95% CI for HR is <1.4327, non-inferiority margin of 13% in 15 m PFS • One-sided test, power 80%, 5 % significance • 192 events are required, drop-out rate of 10%, 344 patients required • As a general comment non-inferiority studies should not only consider PFS but OS

SOX vs COX in mCRC: Patients population • Adhere to the CONSORT disposition • Populations: - intention-to-treat - per protocol - safety

SOX vs COX in mCRC: Efficacy data Progression-free Survival Overall Survival FA set HR = 0.760 [0.594, 0.973] P-value = 0.0286 Median : 7.2 vs. 6.2 m FA set HR = 0.897 [0.638, 1.260] P-value = 0.5298 Median : 20.9 vs. 19.9 m

SOX vs COX in mCRC: Safety profile • “SOX regimen showed favorable safety profiles compared to COX regimen”

SOX vs COX in mCRC: Safety profile • All toxicities but skin more frequent in SOX than COX

SOX vs COX in mCRC: Critique and implications • Design: • the trial was underpowered to detect non inferiority • a margin of 1.43 is a very large margin • for NI studies, OS is the more usual primary endpoint • Results: • Matured results, with trends towards superiority on both PFS and OS • Safety: not well defined, grade 2-3-4-5 all together • Complete follow-up, safety description and treatment details are needed • SOX may be a reasonable option in those countries where S1 is approved

Figitumumab (CP-751,871) in mCRC

Cixutumumab (IMC-A12) ± Cetuximab • Randomized, phase II study of the IGF-1R MoAbIMC-A12 (cixutumumab), with or without cetuximab, in patients with cetuximab- or panitumumab-refractory mCRC (NCT00503685)1: • Negative • 1 PR out of 41 patients treated with the combo (not all KRAS wt) 1 Reidy et al, J Clin Oncol 2010

Dalotuzumab (MK-0646) + Cetuximab Amended for KRaswild type; N=344 patients • Negative: inferior PFS & OS for experimental arms • Biomarker sub-analysis in progress DJ Watkins et al. Clinical Science Symposium. A#3501. J ClinOncol 2011 ClinicalTrials.gov

PmabvsPmab+ AMG479 vsPmab + AMG102 Part 1 (Phase 1b)a Part 2 (Phase 2)b Part 3 (Phase 2)c Panitumumab+ Rilotumumab(AMG 102) Q2W R A N D O M I Z E R A N D O M I Z E Panitumumab+ Rilotumumab(AMG 102) Q2W Rilotumumab (AMG 102) Q2W Panitumumab+ Ganitumab(AMG 479) Q2W Amgen Trial 20060447 NCT00788957 Ganitumab (AMG 479) Q2W Panitumumab+ Placebo Q2Wd C Eng et al. Clinical Science Symposium. A#3500. J ClinOncol 2011 ClinicalTrials.gov

Anti-IGF1R MoAbs in mCRC: clinical implications • Two large phase II studies negative • Two randomized phase II/III studies negative • No further development in mCRC permited unless a dependence/predictive signature is characterized • Ligands IGF-1 & -2 • IGF1R • IGFBPs • …

ACT: maintenance tx in mCRC. Study design • Primary objective: • PFS • Secondary objectives: • OS • ORR 1sttx • Safety FOLFIRI / FOLFOX / XELIRI / XELOX (Investigator´s choice) + bev (2.5 mg/kg*w) 18 weeks PD Curative surgery • Statistical design: • mPFS 3  5 m, HR 0.6 • Power 90%, p<.05 (2s) • 168 events, 240 pts planned • Power 80%, 126 events • Stratification: • OXL-based chemo • Objective response CR PR SD Bev (7.5 mg/kg) q3w Erlo (150 mg p.o.) qd Bev(7.5 mg/kg) q3w

ACT: maintenance tx in mCRC. Results 1.00 • Bev + Erlotinibvs Bev: mPFS 4.2  5.9; HR 0.81, p=0.24 • Combined treatment more toxic but manageable • ACT2 study: - KRAS WT: Bev + erlotinibvs Bev - KRAS MT: Bev + low dose CPC vs Bev Estimated probability 0.75 0.50 HR 0.81 (0.57-1.15) p=0.24 0.25 0.00 0 5 10 15 20 Months

Enzastaurin: maintenance tx in mCRC. Study design FOLFIRI / FOLFOX (Investigator´s choice) + bev (2.5 mg/kg*w) 12 weeks • Primary objective: • PFS • Secondary objectives: • OS • Safety PD • Statistical design: • mPFS 5.5  7.5 m • Power 60%, p<.2 (1s) • Stratification: • OXL-based chemo • Objective response CR PR SD • Enzaustarin: • Oral serine/threoninekinase • inhibitor targeting PKCβ ENZ + 5FU/LV + Bev Placebo + 5FU/LV + Bev Enzastaurin 1125 mg/day gTID (125 mg tablets) on Day 1 of Cycle 1 (loading dose) and 500 mg/day given BID thereafter

Enzastaurin: rationale in mCRC • Suppresses signaling via PKCβand PI3K/AKT • Inhibits phosphorylation of downstream signal proteins, including GSK3b • Suppresses tumor growth, proliferation, and angiogenesis • Inhibits multiple PKC isoforms • Highly selective for PKCβ: IC50=0.006 mM • IC50 (mM): PKCa=0.039, PKCg=0.83, PKCe=0.110 • Promotes apoptosis • Promotes apoptosis • Preclinical activity: only HCT-116, synergistic over bevacizumab, no evaluation with 5FU Enzastaurin A Novel, AcyclicBisindolylmaleimide

Enzaustarin: maintenance tx in mCRC. Results • mPFS from randomization 5.8 vs 8.1 m; HR=1.35, 95% CI: 0.84-2.16; p=0.9 (1s) • mPFS from start of first-line therapy 8.9 vs 11.3 m; HR=1.39, 95% CI: 0.86-2.23; p=0.9 (1s) • Low grade toxicity, but pulmonary embolism (7%) and G 3/4 thrombosis in 18% • Safety or activity interaction? PFS Time From Randomization (Months)

Maintenance treatment in mCRC • Unmet need • Several approaches being evaluated • Targeted therapies: • Bevacizumab: MACRO, CAIRO-3, DREAM (+ erlotinib), AIO-ML21768 • Cetuximab: MACRO-2 • Other targeted therapies • Less complex/toxic chemotherapy • The concept is valid and feasible

FCGR polymorphisms on cetuximab efficacy FcRIIa 131 histidine (H)/arginine (R) FcRIIIa 158 valine (V)/phenylalanine (F) Breast cancer FcRIIa 131 histidine (H)/arginine (R) FcRIIIa 158 valine (V)/phenylalanine (F) NHL A Musolino et al. J ClinOncol 2008;26:1789-1796; WK Weng et al. J ClinOncol 2003;21:3940-3947

FCGR polymorphisms on cetuximab efficacy Colon cancer • Limited series available: 39 and 69 patients • FcRIIIa and FcRIIa polymorphisms predictive independently of KRAS mutation status FcRIIIa 158 valine (V)/phenylalanine (F) FcRIIa 131 histidine (H)/arginine (R) FcRIIIa 158 valine (V)/phenylalanine (F) FcRIIa 131 histidine (H)/arginine (R) FcRIIa 131 histidine (H)/arginine (R) W Zhang et al. J ClinOncol 2007;25:3712-3718; F Bibeau et al. J ClinOncol 2009; 27:1122-1129

FCGR polymorphisms on cetuximab efficacyEuropean Consortium • Characteristics: • Largest series: KRAS WT 591 patients, KRAS MT 261 patients • Homogeneous population treated with cetuximab and irinotecan in the refractory setting • Results: • No correlation between FCGRIIa & IIIaSNPs and efficacy in unselected patients and KRAS WT population • In the KRAS MT population potential benefit in FCGRIIIa SNPs FF vs non-FF: • DCR 61.5% vs 47.9%, p=0.049 (Fisher's Exact Test, 2-sided) • Increase in OS: mOSFF 39 w vs non-FF 31 w, p=0.005 • Hypothesis: ADCC in the non-sensitive population by signal transduction inhibition (KRAS MT)?

PICCOLO: Ir vs. IrPan – Analysis populations Primary analysis population (red circle, n=460): KRAS12-13,61-wt, unpretreated “Double wild-type” (n=384): confirmed to also be BRAF-wt “All wild-type” (n=265): wt at KRAS12-13,61 KRAS146 NRAS12-13,61and BRAF

PICCOLO: PFS by molecular populations KRAS wt: 460 pts, 399 events HR=0.78 (0.64, 0.95), p=0.01 Double wt : 348 pts, 304 events; HR=0.73 (0.58, 0.92), p=0.01 All wt: 264 pts, 229 events; HR=0.70 (0.53, 0.91), p=0.01 BRAFmut: 63 pts, 59 events; HR=1.47 (0.85, 2.56) NRAS mut: 21 pts, 19 events HR=2.18 (0.74, 6.39) KRAS146mut: 17 pts, 15 events HR=0.56 (0.13, 2.48) Anymut: 99 pts, 91 events HR=1.38 (0.89, 2.13) *Adjusted HRs, 95% CIs IrPanbetterIr better

PICCOLO: OS by molecular populations KRAS wt: 460 pts, 312 events HR=0.91 (0.73, 1.14), p=0.44 Double wt : 348 pts, 230 events; HR=0.87 (0.67, 1.13), p=0.30 All wt: 264 pts, 171 events; HR=0.86 (0.63, 1.16), p=0.32 BRAFmut: 63 pts, 53 events; HR=2.03 (1.13, 3.64) NRAS mut:21 pts, 15 events HR=4.59 (1.19, 17.67) KRAS146mut: 17 pts, 14 events HR=1.32 (0.30, 5.81) Anymut:99 pts, 80 events HR=2.03 (1.26, 3.28) *Adjusted HRs, 95% CIs IrPanbetterIr better

PICCOLO: OS by molecular populations Ir IrPan Ir IrPan BRAF mut HR=2.03 [1.13, 3.64] p=0.017 63 patients, 53 events Any Mutation HR=2.03 [1.26, 3.28] p<0.01 99 patients, 80 events

PICCOLO: molecular populations. Clinical implications • Patients with BRAF-mut tumors had a poor prognosis and in this study appeared to be further harmed by the addition of panitumumab • Overall, 99/460 (22%) patients with KRAS12-13,61-wt tumors had activating mutations in the RAS/RAF pathway, and had significant OS detriment with panitumumab: HR=2.03 (1.26-3.28). • International Academic/Pharma collaboration is required to evaluate/corroborate this results in randomized studies • Example: European consortium1 • Potential implications in patient’s profile W De Roock et al. Lancet Oncol 2010;11:753-762

Acknowledgments • Thanks to the authors for providing all the presentations and answers to my queries • Special thanks to: • Daniel Sargent • Andres Cervantes • Sabine Tejpar

Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528

Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528

Presentation Transcript

Colorectal Cancer

COLORECTAL CANCER

Colorectal cancer

Colorectal cancer

Colorectal Cancer

GI POSTER SESSION ESOPHAGEAL CANCER

COLORECTAL CANCER

Colorectal cancer