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Systemic Treatment of Metastatic Colorectal Cancer: Living with a Moving Landscape Neal J. Meropol, MD Fox Chase Cancer Center May 16, 2005 History of Systemic Therapy for Colorectal Cancer Patient Benefit ? 5-FU Modulation Biologics New Cytotoxics 1980’s 1990’s 2000’s bevacizumab 5-FU/leucovorin capecitabine oxaliplatin cetuximab capecitabine/irinotecan irinotecan FOLFIRI IFL FOLFOX cetuximab/irinotecan capecitabine/oxaliplatin Treatment Summary: Front-Line • Capecitabine = 5-fluorouracil • 2 drugs are better than 1 – Irinotecan doubles response rate and improves survival by a few months when added to 5FU/LV – Oxaliplatin doubles response rate and improves TTP by a few months when added to 5-FU/LV • Irinotecan/FU/LV = oxaliplatin/FU/LV • Bevacizumab improves survival when added to irinotecan/FU/LV; improves TTP with 5-FU/LV Treatment Summary: 2nd-, 3rd-Line • Irinotecan improves survival (vs. BSC) by a few months as second-line therapy • Oxaliplatin+FU/LV improves RR and TTP over either alone • Bevacizumab improves survival when added to oxaliplatin/FU/LV • Cetuximab and panitumumab have modest single agent activity • Cetuximab + irinotecan improves RR% over cetuximab alone Survival with Metastatic Colorectal Cancer: Chemotherapy With antibodies? FOLFOX FOLFIRI IROX IFL Grothey, A. et al. J Clin Oncol; 22:1209-1214 2004 Some Practical Clinical Questions • • • • • • • Capecitabine combinations? Optimal second line? Combinations of biologics? Cetuximab front-line? Cetuximab before irinotecan failure? Non-irinotecan cetuximab combinations? Bevacizumab for life? Questions Addressed Today • Capecitabine combinations? • Optimal second line? • Combinations of biologics? Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer: results of the safety and efficacy analysis Arkenau et al. ASCO 2005, #3507 FUFOX vs. CAPOX: Results • Similar toxicity profile; ~25% severe neuropathy • Equivalent PFS, 7.0 (C) vs. 8.0 (F) months (HR=1.19, 95% CI 0.97–1.48, p=0.11) • Equivalent median S, 16.3 (C) vs. 17.2 (F) months (HR=1.05, 95% CI 0.79-1.41, p=0.72) • Response rate ~50% in both arms • Note: potential differences in tolerated doses in different populations (e.g. Cassidy JCO 2004, Shields Cancer 2004) CAPOX vs. FUFOX Overall Survival Estimated probability 1.0 CAPOX (n=238) FUFOX (n=230) 0.8 Median 16.3 months 17.2 months HR = 1.05 (95% CI: 0.79–1.41) p=0.72 (Log-rank) 0.6 0.4 0.2 0 0 20 40 60 80 Weeks 100 120 140 N9841: A randomized phase III equivalence trial of irinotecan (CPT-11) versus oxaliplatin/5-fluorouracil /leucovorin (FOLFOX4) in patients with advanced colorectal cancer previously treated with 5FU Pitot et al. ASCO 2005, #3506 N9841 Results • Equivalent overall survival, 14.7 (I) vs. 13.5 (FOLFOX) months (HR=1.05, 95% CI 0.91.3) • FOLFOX less toxic (except neuropathy) • Response rate higher with FOLFOX (27% vs 15%, p<0.01) • TTP equivalent (trend favors FOLFOX, 5.2 vs. 4 months, p=0.10) N9841: Overall Survival 100 90 80 % Alive 70 60 50 40 30 CPT-11 20 N = 245 FOLFOX 10 N = 246 0 0 2 4 6 8 10 12 14 16 18 20 Months from Registration 22 24 Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer Saltz et al. ASCO 2005, #3508 EGFR Antibodies Block Ligand Binding and Downstream Signaling Antibody Pao, W. et al. J Clin Oncol; 23:2556-2568 2005 Rational Combinations EGFR and VEGF Inhibitors VEGF Bevacizumab + Cetuximab in Colorectal Cancer Cetux/Bev/Irinotecan Partial Response 15/41 (37%) Median TTP 7.9 months Range (1+ to 16+ months) Cetux/Bev Partial Response 8/40 (20%) Median TTP 5.6 months Range ( 1+ to 12+ months) Saltz et al. ASCO 2005 Rational Combinations EGFR + IGF-1R or HER2 Inhibitors EGFR and AKT/mTOR Inhibitors EGFR and RAS/Raf/MEK/ MAPK Inhibitors What have we learned? 1. 2. 3. For many patients, metastatic colorectal cancer is no longer an acute illness There is more than one correct way to use drugs with modest activity in unselected populations The selection of new combinations should no longer be based primarily upon avoidance of overlapping toxicities, but rather an appreciation of colorectal cancer as a network of interrelated processes The Big Questions that Should Guide Future Clinical Research: How do these drugs work and who should get them? Matchmaking is Science Potential Sources of Variability • The tumor – Target characteristics – Target relevance – Drug disposition – Resistance mechanisms • The patient – Drug metabolism – Normal tissue sensitivity How Can Clinical Investigators Deal with a Rapidly Changing Landscape? (This is not 1995) • Undertake in vivo pharmacodynamic assessment to ensure target acquisition and define mechanism of action during early clinical development • Be forward-thinking in clinical trial design; this requires acceptance of risk • Accept that toxicity evaluation will not be complete before phase III investigation • Work with patient advocates; ensure relevance to those asked to participate • Bank biologic material; there is now less redundancy and more potential for missed opportunities Can Society Afford State-of-the-Art Cancer Treatment? Neal J. Meropol, MD, Fox Chase Cancer Center, Chair Sue Hellmann, MD, MPH, Genentech Inc. Kevin A. Schulman, MD, MBA, Duke University Barry Straube, M.D., CMS Level 4, Valencia Room, 415A 12:00-1:15 May 16, 2005