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A Report from ASCO GI 2008 Up-to-Date Review of the Treatment of Metastatic Colorectal Cancer

A Report from ASCO GI 2008 Up-to-Date Review of the Treatment of Metastatic Colorectal Cancer. Edward Chu, MD Professor of Internal Medicine and Pharmacology Chief, Section of Medical Oncology Yale Cancer Center Yale University School of Medicine New Haven, CT. Outline.

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A Report from ASCO GI 2008 Up-to-Date Review of the Treatment of Metastatic Colorectal Cancer

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  1. A Report from ASCO GI 2008Up-to-Date Review of the Treatment of Metastatic Colorectal Cancer Edward Chu, MDProfessor of Internal Medicine and Pharmacology Chief, Section of Medical Oncology Yale Cancer CenterYale University School of Medicine New Haven, CT

  2. Outline • Cytotoxic chemotherapy • FOLFOX and neurotoxicity • FOLFOX versus XELOX • Integration of biologics with cytotoxic chemotherapy • Bevacizumab • Bevacizumab plus panitumumab • Biomarker development for anti-EGFR antibodies

  3. Abstract 280 Effect of Intravenous Calcium and Magnesium vs Placebo on Response to FOLFOX+bevacizumab in the CONcePT Trial Hochster HS, Grothey A, Shpilsky A, Childs BH

  4. RANDOM I Z E 1° Endpoint: TTF for continuous vs. intermittent oxaliplatin mFOLFOX7/bev + placebo Continuous Oxaliplatin mFOLFOX7/bev + Ca2+/Mg2+ • Exclusion Criteria: • Prior exposure to bev and/or oxaliplatin • Peripheral neuropathy grade >1 mFOLFOX7/bev + placebo Intermittent Oxaliplatin mFOLFOX7/bev + Ca2+/Mg2+ CONcePT : Schema mFOLFOX7/bev: oxaliplatin 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr, 5-FU 2400 mg/m2 over 46 hours, bevacizumab 5 mg/kg over 30-90 minutes, Day 1 biweekly Ca2+/Mg2+: 1 g calcium gluconate/1 g magnesium sulfate over 30 min before and after oxaliplatin Intermittent: alternating between 8 cycles with oxaliplatin and 8 cycles with 5-FU/LV only

  5. RANDOM I Z E 1° Endpoint: TTF for continuous vs. intermittent oxaliplatin mFOLFOX7/bev + placebo Continuous Oxaliplatin mFOLFOX7/bev + Ca2+/Mg2+ • Exclusion Criteria: • Prior exposure to bev and/or oxaliplatin • Peripheral neuropathy grade >1 mFOLFOX7/bev + placebo Intermittent Oxaliplatin mFOLFOX7/bev + Ca2+/Mg2+ CONcePT : Schema Study closed early due to negative impact of Ca2+/Mg2+on efficacy of mFOLFOX7/bev (int and cont) found by IDMC during unplanned interim analysis mFOLFOX7/bev: oxaliplatin 85 mg/m2 over 2 hr, LV 200 mg/m2 over 2 hr, 5-FU 2400 mg/m2 over 46 hours, bevacizumab 5 mg/kg over 30-90 minutes, Day 1 biweekly Ca2+/Mg2+: 1 g calcium gluconate/1 g magnesium sulfate over 30 min before and after oxaliplatin Intermittent: alternating between 8 cycles with oxaliplatin and 8 cycles with 5-FU/LV only

  6. CONcePT : Clinical Efficacy

  7. CONcePT: Conclusions • Two-factor logistic regression exploratory model of response data revealed no significant relationship between use of Ca2+/Mg2+ and response • Future reports of neuroprophylaxis await pending data

  8. Abstract 347 Diabetes Mellitus and the Incidence and Time to Onset of Oxaliplatin-Induced Peripheral Sensory Neuropathy (PSN) in Patients with Colorectal Cancer: A Pooled Analysis of Three Randomized Studies Ramanathan RK, André T, Rothenberg ML, de Gramont A, Tournigand C, Goldberg RM, Gupta S

  9. Pooled Analysis Conducted pooled analysis of data from randomized clinical trials including FOLFOX4 treatment arm EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC EFC2962: Phase II/III study of LV5–FU2 + oxaliplatin PSN data from the overall study population with or without diabetes were analyzed for: Incidence and time to onset of PSN (Kaplan-Meier) Trends indicating clinically relevant differences in the incidence and severity of PSN (Kaplan-Meier) Ramanathan et al, ASCO GI 2008, abstract 347.

  10. Incidence and Severity of PSN Ramanathan et al, ASCO GI 2008, abstract 347.

  11. Conclusions Patients with diabetes mellitus do not have an increased risk of developing cumulative neurotoxicity

  12. Abstract 341 XELOX vs. FOLFOX-4: Update of Efficacy Results from XELOX-1/NO16966, a Randomized Phase III Trial of First-Line Treatment for Patients with Metastatic Colorectal Cancer (MCRC) Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, A. Figer A, Wong R, Koski S, Sirzen F, Gilberg F, Saltz L

  13. Phase III NO16966 TrialSchema RecruitmentJune 2003 – May 2004 RecruitmentFeb 2004 – Feb 2005 XELOX (N = 317) XELOX + Placebo (N = 350) XELOX + Bevacizumab (N = 350) FOLFOX4 (N = 317) FOLFOX4 + Placebo(N = 351) FOLFOX4 + Bevacizumab (N = 349) Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III databecame available (N = 1400) Initial 2-armopen-label study (N = 634) Cassidy et al, ASCO GI 2008, Abstract 341.

  14. XELOX-1/NO16966 TrialAdverse Events Cassidy et al, ASCO GI 2008, Abstract 341.

  15. XELOX-1/NO16966 TrialEfficacy Results Cassidy et al, ASCO GI 2008, Abstract 341.

  16. Abstract 340 Efficacy of Capecitabine vs. 5-FU in Colorectal and Gastric Cancer: Meta-analysis of Survival in 6 Clinical Trials Cassidy J, Rothenberg M, Saltz L, Twelves C, Van Cutsem E, Hoff P, Kang Y-K, Sirzen F, Gilberg F, Cunningham D

  17. Meta-Analysis: Capecitabine vs 5-FU • Included individual patient data from 6 phase III trials comparing the efficacy of capecitabine and 5-FU in metastatic colorectal and gastric cancers • Main endpoint was overall survival • Assessment completed with unstratified and stratified (by study) data • Included 6,171 patients (3,074 received 5-FU-based regimens and 3,097 received capecitabine-based regimens) • Unstratified data found a median OS of 23.1 and 22.4 months for patients who received capecitabine and 5-FU, respectively (HR = 0.96) Cassidy J et al, ASCO GI 2008, abstract 340.

  18. Meta-Analysis: Stratified OS Analysis Hoff PM et al. JCO 2001; 19:2282-92. Van Cutsem E, et al. JCO 2001; 19:4097-106. Twelves C, et al. N Eng J Med 2005; 352:2696-704. Kang YK, et al, ESMO 2006 (abstract 1072O). Cassidy J, et al. ASCO 2007 (abstract 4030). Rothenberg ML, et al. ASCO 2007 (abstract 4031). Cassidy J et al, ASCO GI 2008, abstract 340.

  19. Conclusions • Findings of meta-analysis suggest: • Equivalency of capecitabine and 5-FU in the treatment of adjuvant and metastatic colorectal cancer • Equivalency of capecitabine and 5-FU in the treatment of metastatic gastric cancer • Equivalency of capecitabine and 5-FU is supported by updated results of the NO16966 trial comparing capecitabine and 5-FU as treatment for metastatic colorectal cancer

  20. Abstract 342 Capecitabine and Oxaliplatin as First-Line Treatment in Patients with MCRC: A Meta-analysis of Randomized Phase II-III Trials Arkenau H-T, Arnold D, Diaz-Rubio E, Douillard J-Y, Martoni A, Grothey A, Hinke A, Schmiegel W, Schmoll H-J, Porschen R

  21. Meta-Analysis: Comparing PFS of Capecitabine- and 5-FU-Containing Regimens 1. Cassidy J, et al. ASCO 2007 (abstract 4030). 2. Porschen R, et al. J Clin Oncol 2007:4217-4223. 3. Díaz-Rubio E, et al. J Clin Oncol 2007:4224-4230. 4. Ducreux M, et al. ASCO 2007 (abstract 4029). 5. Martoni A, et al. Eur J Cancer 2006: 3161-3168. Arkenau HT, et al, ASCO GI 2008, abstract 342.

  22. Conclusions • Findings of meta-analysis suggest non-inferiority of capecitabine/oxaliplatin compared to 5-FU/oxaliplatin, based on PFS analysis and combination regimens.

  23. Abstract 350 Preliminary Efficacy of Bevacizumab with First-Line FOLFOX, XELOX, FOLFIRI and Fluoropyrimidines for MCRC: First BEAT Berry S, Cunningham D, Michael M, Kretzschmar A, Rivera F, DiBartolomeo M, Mazier M, Van Cutsem E, on behalf of the First BEAT investigators

  24. First BEAT: Study Schema Bevacizumab: 5 mg/kg Q2W or 7.5 mg/kg Q3W Endpoints: safety and efficacy Median follow-up 22.9 months First-line metastatic CRC (1,965) Bevacizumab + standard chemotherapy PD Berry et al, ASCO GI 2008, abstract 350.

  25. Serious BEV-Related Adverse Events Berry et al, ASCO GI 2008, abstract 350.

  26. First BEAT: Clinical Efficacy (PFS) Median PFS Overall (N = 1914) 10.9 FOLFIRI (N = 503) 11.6 FOLFOX (N = 552) 11.2 XELOX (N = 346) 11.0 5-FU/Capecitabine (N = 300) 8.6 Berry et al, ASCO GI 2008, abstract 350.

  27. Abstract 363 First-line Irinotecan, Oxaliplatin and Infusional 5FU/LV (FOLFOXIRI) in Combination with Bevacizumab (BV) in MCRC Patients (pts): A Phase II Study by the GONO Group Masi G, Loupakis F, Baldi G, Fornaro L, Di Leo A, Ciarlo A, Amoroso D, Granetto C, Di Donato S, Falcone A

  28. Study Design • Phase II trial evaluating first-line therapy with FOLFOXIRIplus Bev in patients with initially unresectable mCRC • Primary endpoint: PFS rate at 10 months Masi et al, ASCO GI 2008, abstract 363.

  29. First-Line Bev/FOLFOXIRI: Safety Masi et al, ASCO GI 2008, abstract 363.

  30. Bev/FOLFOXIRI: Clinical Efficacy Masi et al, ASCO GI 2008, abstract 363.

  31. Bev/FOLFOXIRI: Conclusions • First-line therapy with bevacizumab/FOLFOXIRI associated with high response rates (76%) and 100% tumor control, in patients with MCRC • High response rates coincided with high R0 resection rate in initially unresectable patients • Grade 3/4 toxicities included nausea, diarrhea, stomatitis, neutropenia, anemia, neurotoxicity, hypertension, deep vein thrombosis, and cardiac ischemia

  32. Abstract 273 An Updated Analysis of Safety and Efficacy of Oxaliplatin (Ox)/bevacizumab (bev) +/- Panitumumab (pmab) for First-line Treatment (tx) of MCRC from a Randomized, Controlled Trial (PACCE) Hecht J. R., Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, Shahin S, Griffin T

  33. PACCE Phase III Trial Panitumumab + Bevacizumab Ox-based CT (e.g., FOLFOX) N = 800 Inv choice S C R E E N I N G R A N D O M I Z E 1:1 Bevacizumab Panitumumab + Bevacizumab Iri-basedCT (e.g., FOLFIRI) N = 200 Inv choice 1:1 Bevacizumab Stratification Factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs Tumor assessments: Q12W until disease progression or intolerability

  34. FOLFOX Chemotherapy: Efficacy Hecht et al, ASCO GI 2008, abstract 273.

  35. PACCE Trial: Grade 3/4 Toxicity Hecht et al, ASCO GI 2008, abstract 273.

  36. Abstract 279 Interim Results from PACCE: Irinotecan (Iri)/bevacizumab (bev) + Panitumumab (pmab) as First-line Treatment (tx) for MCRC Hecht J. R., Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, Suzuki S, Griffin T

  37. FOLFIRI Chemotherapy: Efficacy Hecht et al, ASCO GI 2008, abstract 279.

  38. PACCE FOLFIRI Chemotherapy: Discontinuation of Treatment Hecht et al, ASCO GI 2008, abstract 279.

  39. PACCE: Safety Analysis of FOLFIRI Arms Hecht et al, ASCO GI 2008, abstract 279.

  40. PACCE Trial: Conclusions • Addition of panitumumab to oxaliplatin-containing chemotherapy+bevacizumab worsened PFS and increased toxicity • Panitumumab added to irinotecan modestly increased response, although PFS and OS were similar for both treatment arms • Toxicity of panitumumab/bev-iri was considerable, additionally causing 2% grade 5 infections and gastrointestinal perforation, and 1% grade 5 pulmonary embolism • Most patients discontinued treatment for non-progressive events • Panitumumab/bev-iri improved response rates (54% vs. 47%) in patients with wild type KRAS tumor status • Evaluation of toxicity is ongoing

  41. Role of K-RAS Mutations as Predictive Biomarker • K-RAS: Downstream signalling molecule in EGFR signalling pathway1 • Lower response to erlotinib and gefitinib in NSCLC2,3 – erlotinib: 8% responders in patients with mutations vs 26% in wild-type K-RAS – gefitinib: 24% refractory tumors with K-RAS mutationsvs 0% in drug-sensitive tumours (P = 0.02) • Lower response to cetuximab in CRC4 – 0% responders in patients with mutations vs 49% in non-mutated patients (P < 0.001) 1Calvo & Baselga, J Clin Oncol 2006; 14: 2158.2Eberhard et al, J Clin Oncol 2005; 23: 5900.3Pao et al, PLoS Med 2005; 2: e17.4Lièvre et al, AACR Annual Meeting 2007; Abstract 5671.

  42. Abstract 278 Panitumumab Efficacy and Patient-Reported Outcomes in MCRC Patients with Wild-Type KRAS Tumor Status Amado R, Wolf M, Freeman D, Peeters M, Van Cutsem E, Siena S, Suggs S, Devercelli G, Woolley M, and Chang D

  43. KRAS Analysis of a Phase III Trial of Panitumumab as Salvage Therapy for MCRC RANDOMIZE Panitumumab 6.0 mg/kg Q2W + BSC PD Optional Crossover BSC PD • Stratification • ECOG score (0-1 vs. 2) • Geographic region (Western EU vs. Central & Eastern EU vs. Rest of World) Van Cutsem E et al. J Clin Oncol 25:1658–1664, 2007.

  44. Molecular Composition of Treatment Arms Screened N = 1,040 Tumors screened for KRAS mutation status using DxS, LTD kit Randomized N = 463 Randomized to BSC alone N = 232 Randomized to panitumumab + BSC N = 231 Excluded from KRAS analyses (missing or unevaluable) N = 36 KRAS mutant N = 84 KRAS mutant N = 100 WT KRAS N = 124 WT KRAS N = 119 Received P’mab in X-over protocol N = 77 Received P’mab in X-over protocol N = 90 Amado 2008 ASCO GI abstract #278 BSC = Best supportive care; WT = wild-type

  45. Percent Decrease of Target Lesions in KRAS Evaluable Patients Mutant Wild-Type 160 160 140 140 PR (0%) SD (12%) PD (70%) PR (17%) SD (34%) PD (36%) 120 120 100 100 80 80 60 60 Pmab + BSC % Change % Change 40 40 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 Patient Patient 160 160 140 140 PR (0%) SD (8%) PD (60%) PR (0%) SD (12%) PD (75%) 120 120 100 100 80 80 60 60 BSC Alone 40 40 % Change % Change 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 Patient Patient Amado et al, ASCO GI 2008, abstract 278. BSC = Best supportive care; Pmab = panitumumab

  46. KRAS Mutation Status and Efficacy of Single Agent Panitumumab BSC, basic supportive care; NR, not reported Amado et al, ASCO GI 2008, abstract 278.

  47. Conclusions • Salvage single agent panitumumab significantly (P < .0001) improved PFS in patients with KRAS wild type tumors with no benefit in those having mutant KRAS tumors • Only patients with wild type KRAS benefited from single agent panitumumab in the salvage setting • Long-term outcome of patients was primarily dictated by KRAS mutation status • Future studies will focus on prospective analysis of the efficacy of panitumumab-containing combination therapy in patients with wild type and mutant KRAS tumors

  48. Abstract 343 Panitumumab Efficacy in Patients with MCRC with Low or Undetectable Levels of Epidermal Growth Factor Receptor: Final Efficacy and KRAS Analysis Hecht JR, Mitchell EP, Baranda J, Richards D, Reiner M, Stout S, Amado RG

  49. Trial Design • Phase II single-arm, open-label study • Patients received panitumumab 6 mg/kg (Q2W) until disease progression or unacceptable toxicity • Previous analyses indicated that panitumumab efficacy is independent of tumor EGFR expression levels (Mitchell, ASCO 2007 abstract 4082, Hecht, ASCO GI 2007 abstract 350) • Exploratory analysis of KRAS mutation status – Total of 203 pts enrolled – EGFR expression levels available for 195 pts – KRAS mutation status available for 171 pts (55% wild type, 45% mutant) Hecht et al, ASCO GI 2008, abstract 343.

  50. Panitumumab in Low EGFR Expressors: KRAS and Efficacy Hecht et al, ASCO GI 2008, abstract 343.

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