1. 2007-2008 Lower GI Overview Chair: Charles D. Blanke, M.D., F.A.C.P. Systemic Therapy Provincial Program Leader, B.C. Cancer Agency Chief, Division of Medical Oncology, University of British Columbia

2. What’s New Re: Large Bowel Malignancy Update on Systemic Therapy for Metastatic Disease: Charles D. Blanke, M.D. Modern Adjuvant Therapy for Resected Colon Cancer: John R. Zalcberg, M.D., Ph.D. Review of Radiotherapeutic Approaches to Rectal Cancer: Claus Roedel, M.D. Panel Discussion/Questions

3. ASCO Potential Conflict of Interest Disclosures (Blanke) Consultant or Advisory Role: Imclone, Pfizer, Roche, Sanofi, Raven Biotech Research Funding: Novartis, Sanofi-Aventis Expert Testimony: Private entities

4. Update on Systemic Therapy for Metastatic Colorectal Cancer Background What’s New in Chemotherapy Selection What’s New in Targeted Therapy (Biologic) Selection What’s New in Scheduling

5. Chemotherapy Offers a Survival Advantage over BSC in mCRC Scheithauer BMJ 306:752, 1993

6. 5FU: All We had for 40 Years Antimetabolite pyrimidine antagonist designed and synthesized 1957 Most extensively studied and used drug GI oncology Poor single-agent response rate (5-18%) We can make it better, but not much better -Adding leucovorin improves response rate (23%) and survival (~10-12 months) -Giving by infusion improves survival, decreases toxicity

7. US Approved Agents in mCRC YEAR1 ST LINESALVAGE 1991LV 1996, 1998Irinotecan 2000Irinotecan 2001Capecitabine 2002Oxaliplatin 2004Oxaliplatin, Bevacizumab Cetuximab 2006Bevacizumab, Panitumumab

8. 88 How Much Better Do We Do By Adding a New Drug: Summary Efficacy Data on Irinotecan + 5- FU/LV SaltzDouillard Response Rate39%41% Time to Progression 7 mos6.7 mos Overall Survival14.4 mos16.8 mos Saltz N Eng J Med 343:905, 2000 Douillard Lancet 355:1041, 2000

9. 99 How About Oxaliplatin: Summary Phase III Trial of First- Line FOLFOX4 vs. LV5FU2 (Efficacy) LV5FU2 FOLFOX4P Value ORR (%)2251.0001 PFS (mo)6.29.0.0003 OS (mo)14.716.2.12 de Gramont J Clin Oncol 18:2938, 2000

10. 10 Phase III Trial of First-Line FOLFIRI/FOLFOX6 FOLFOX6*  FOLFIRI † FOLFIRI  FOLFOX6 Regimens: oxaliplatin* (100 mg/m 2 ) or irinotecan † (180 mg/m 2 ) IV + LV 200 mg/m 2 over 2 hours d 1, 5-FU 2,400-3,000 mg/m 2 over 46 hours Primary end point: TTP Secondary end points: ORR, safety n=113 Tournigand J Clin Oncol 22:229, 2004 RANDOMIZERANDOMIZE

11. 11 Efficacy Arm A-FOLFIRIArm B-FOLFOXP 1st line ORR (%) 5654NS 1st line PFS (mo) 8.58.0.26 2nd PFS (mo) 14.210.9.64 Overall Survival (mo) 21.520.6.99

12. Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI vs. FOLFIRI in the G.O.N.O. randomized phase III study in metastatic colorectal cancer. 2007 A.S.C.O. Annual Meeting Chicago (USA), June 1-5 A. Falcone 1,3, M. Andreuccetti 1, I. Brunetti 2, S. Ricci 2, C. Barbara 1, W. Evangelista 4, V. Passeri 5, S. Chiara 6, G. Allegrini 1, G. Masi 1 1 U.O. Oncologia Medica, Azienda USL-6, Livorno; 2 U.O. Oncologia Medica, Ospedale S. Chiara, Pisa; 3 Università degli Studi di Pisa, 4 Centro Oncologico ed Ematologico Subalpino, Ospedale S. Giovanni Battista Le Molinette, Torino, 5 Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma, 6 Istituto Nazionale per la Ricerca sul Cancro, Genova ITALY

13. FOLFOXIRI SCHEDULE 5FU flat continuous infusion 3200mg/m 2 L-LV 200 mg/m 2 Oxaliplatin 85 mg/m 2 2 hours Repeated every 14 days CPT-11 165 mg/m 2 48 hours1 hour

14. FOLFOXIRI vs. FOLFIRI: Summary FOLFOXIRIFOLFIRIp Grade 3 diarrhea20%12%NA Grade 3 neutropenia50%28%0.0006 Objective response rate (%)6034<0.001 R0 surgery (%)1560.033 Median OS (mo)23.616.70.042

15. Clinical Impact of FOLFOXIRI Study Not a ton –Not widely used overall, despite modest toxicity and impressive efficacy –?Because trial did not include biologics Modestly commonly used to downstage potential metastasectomy patients

16. Starting Point: Common Uses of Biologics Last Year First-line metastatic disease: FOLFOX or FOLFIRI + bevacizumab –Median OS IFL +/- bev 15.6 vs. 20.3 months* –No real front-line data oxaliplatin-based rx with bevacizumab (TREE-2) Common second-line rx: CPT-11 or FOLFIRI alone or with cetuximab –ORR cetux + CPT-11 vs. cetux: 23% vs. 11% Common “late”-line therapy: cetuximab + CPT-11 or panitumumab –Both antibodies offer PFS or OS benefit over BSC

17. XELOX + placebo n=350 FOLFOX-4 + placebo n=351 XELOX + bevacizumab n=350 FOLFOX-4 + bevacizumab n=349 XELOX n=317 FOLFOX-4 n=317 Initial 2-arm open-label study (n=634) Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III data 8 became available (n=1400) Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 ASCO 2007: XELOX-1 / NO16966 study design Courtesy Dr. Cassidy

18. Cassidy, J. et al. J Clin Oncol; 26:2006-2012 2008 XELOX is non-inferior to FOLFOX-4 for Progression-Free Survival (intent-to-treat population)

19. Chemotherapy with or Without Bevacizumab: Efficacy Bev + chemorxChemorxHazard Ratio (p value) PFS (mo.)9.480.83 (0.0023) PFS CapOX (mo.)9.37.40.77 (0.0026) PFS FOLFOX4 (mo.) 9.48.60.89 (0.1871) OS (mo.)21.319.90.89 (0.077) Saltz J Clin Oncol 26:2013, 2008 Yellow = significant White = not significant

20. NO16966 Take-Home Points Capecitabine is at least as effective as 5FU, even in combination Bevacizumab improves front-line efficacy (PFS) of FPs –Lack of PFS improvement for FOLFOX is interesting –Lack of OS and ORR improvements also interesting –Authors suggested continuing bev until progression important, even if part of chemorx is dropped (e.g., oxaliplatin)

21. The CRYSTAL trial: Efficacy and safety of irinotecan and 5-FU/FA with and without cetuximab in the first-line treatment of metastatic colorectal cancer Eric Van Cutsem*, M Nowacki, I Lang, S Cascinu, I Shchepotin, J Maurel, P Rougier, D Cunningham, J Nippgen, C-H Köhne *University Hospital Gasthuisberg, Leuven, Belgium Courtesy Dr. Eric Van Cutsem PASCO 2007

22. CRYSTAL trial: Study design Stratification factors:  Regions  ECOG PS Populations  Randomized patients n=1217  Safety population n=1202  ITT population: n=1198 FOLFIRI irinotecan (180 mg/m 2 ) + 5-FU 400 mg/m 2 bolus + 2400 mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks Cetuximab + FOLFIRI Cetuximab IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly + irinotecan (180mg/m 2 ) + 5-FU (400 mg/m 2 bolus + 2400 mg/m 2 as 46-hr continuous infusion) + FA every 2 weeks R Untreated EGFR-expressing metastatic CRC Courtesy Dr. Van Cutsem

23. CRYSTAL Trial: Summary FOLFIRIFOLFIRI + CetuximabOdds Ratio/HR (p value) Grade 3/4 Diarrhea (%)10.515.2-- Grade 3 Skin Toxicity (%)0.218.7-- ORR (%)38.746.9(0.0038) Median PFS (mo)*8.08.90.851 (0.0479) RO Resection Rate (%)1.54.33 (0.0034) *Primary objective

24. 24 CRYSTAL Take-Home Points Cetuximab improves efficacy of FOLFIRI Cetuximab works in first-line rx of metastatic CRC Cetuximab can be used as part of “conversion therapy” Not shown: EGFR Ab may not work in patients with mutant ras* - We may need to start testing patients before using cetux or panitum -Current national trials in CRC may need to be modified *ASCO plenary 2008!

25. 25 The Kitchen and Bathroom Sinks: “FOLFOXIRI” with Bev or Cetuximab GI Symposium 2008: Phase II trial of FOLFOXIRI + bev in first- line mCRC (Masi et al.) -23% grade 3 neutropenia; 83% ORR! Same : FOLFIRINOX + cetux in first-line mCRC (Samalin et al.) -3/14 DLT (1 toxic death); 57% ORR (14% CR!) Stay tuned Be careful

26. 26 CAUTION! Emerging Concerns About Combining Chemotherapy and Two Biologics PACCE 1 (chemorx + bev +/- panitumumab): Worse PFS for oxali/bev/pan and CPT/bev/pan vs. drug/bev alone –Lots more toxicity and toxic deaths for combos, too CAIRO-2 2 (Capox + bev +/- cetuximab): Statistically significantly worse PFS with both antibodies –More rash and diarrhea; no major increase in deaths Is there a negative interaction between EGFR- and VEGF- directed antibodies? What about C80405 (current phase III Intergroup study)? 1 GI Symp 2008 2 ASCO 2008

27. SCHEDULING: CAIRO study CKTO 2002-07 Arm A Arm B Randomize capecitabine capecitabine + oxaliplatin irinotecan capecitabine + oxaliplatin capecitabine + irinotecan 1 st line 2 nd line 3 rd line Courtesy Punt, PASCO 2007

28. Median overall survival Combination treatment 17.4 months (15.2-19.2) ----------- Sequential treatment 16.3 months (14.3-18.2) p = 0.33 Updated Lancet 370:105, 2007

29. 29 Thoughts on Scheduling: 2007-08 > 1 study has suggested starting out with one drug is OK -Combinations still significantly favored by most oncologists Chemoholidays now mandatory with wide-spread use of FOLFOX -Optimox-2 1 suggested 7 month improvement in OS with use of maintenance chemotherapy instead of full holiday (p = 0.0545) 1 ASCO 2007

30. 30 Update on Systemic Therapy for Metastatic Colorectal Cancer: Conclusions  After a 10-year explosion of new drugs, we have been bereft ofnew agents  Questions still remain re: the optimal chemo- and biologicregimens in first and second-line settings  More aggressive combinations seem to lead to greaterdownsizing of tumor -May equal greater rates of resectability and thus cure

31. 31 Update on Systemic Therapy for Metastatic Colorectal Cancer: Conclusions (cont.) Capecitabine may be substituted for 5FU, alone or incombination regimens Don’t combine antibodies off study The jury remains out on initial combinations versussequential single-agent therapies Selecting agents based on genetic testing is here (ras)!