1. Systemic Treatment of Metastatic Colorectal Cancer: Living with a Moving Landscape Neal J. Meropol, MD Fox Chase Cancer Center May 16, 2005

2. History of Systemic Therapy for Colorectal Cancer ? 5-FU Modulation 1980’s New Cytotoxics 1990’s Biologics 2000’s Patient Benefit

3. 5-FU/leucovorin oxaliplatin irinotecan capecitabine/irinotecan FOLFOX capecitabine/oxaliplatin capecitabine FOLFIRI IFL bevacizumab cetuximab cetuximab/irinotecan

4. 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 5- FU/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

5. Treatment Summary: 2 nd -, 3 rd -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

6. Grothey, A. et al. J Clin Oncol; 22:1209-1214 2004 Survival with Metastatic Colorectal Cancer: Chemotherapy IFL IROX FOLFIRI FOLFOX With antibodies?

7. 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?

8. Questions Addressed Today Capecitabine combinations? Optimal second line? Combinations of biologics?

9. 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

10. 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)

11. CAPOX vs. FUFOX Overall Survival 1.0 0.8 0.6 0.4 0.2 0 020406080100120140 Weeks Estimated probability Median CAPOX (n=238) 16.3 months FUFOX (n=230) 17.2 months HR = 1.05 (95% CI: 0.79–1.41) p=0.72 (Log-rank)

12. 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

13. N9841 Results Equivalent overall survival, 14.7 (I) vs. 13.5 (FOLFOX) months (HR=1.05, 95% CI 0.9- 1.3) 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)

14. N9841: Overall Survival

15. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer Saltz et al. ASCO 2005, #3508

16. Pao, W. et al. J Clin Oncol; 23:2556-2568 2005 EGFR Antibodies Block Ligand Binding and Downstream Signaling Antibody

17. Rational Combinations EGFR and VEGF Inhibitors VEGF

18. 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

19. Rational Combinations EGFR and RAS/Raf/MEK/ MAPK Inhibitors EGFR + IGF-1R or HER2 Inhibitors EGFR and AKT/mTOR Inhibitors

20. What have we learned? 1.For many patients, metastatic colorectal cancer is no longer an acute illness 2.There is more than one correct way to use drugs with modest activity in unselected populations 3.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

21. The Big Questions that Should Guide Future Clinical Research: How do these drugs work and who should get them?

22. Matchmaking is Science

23. Potential Sources of Variability The tumor –Target characteristics –Target relevance –Drug disposition –Resistance mechanisms The patient –Drug metabolism –Normal tissue sensitivity

24. 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

25. 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