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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 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 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 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 Chemotherapy Offers a Survival Advantage over BSC in mCRC Scheithauer BMJ 306:752, 1993 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 US Approved Agents in mCRC YEAR 1991 1996, 1998 2000 2001 2002 2004 2006 1ST LINE LV SALVAGE Irinotecan Irinotecan Capecitabine Oxaliplatin, Bevacizumab Oxaliplatin Cetuximab Bevacizumab, Panitumumab How Much Better Do We Do By Adding a New Drug: Summary Efficacy Data on Irinotecan + 5FU/LV Saltz Douillard Response Rate 39% 41% Time to Progression 7 mos 6.7 mos Overall Survival 14.4 mos 16.8 mos Saltz N Eng J Med 343:905, 2000 Douillard Lancet 355:1041, 2000 8 How About Oxaliplatin: Summary Phase III Trial of FirstLine FOLFOX4 vs. LV5FU2 (Efficacy) LV5FU2 FOLFOX4 P Value ORR (%) 22 51 .0001 PFS (mo) 6.2 9.0 .0003 OS (mo) 14.7 16.2 .12 de Gramont J Clin Oncol 18:2938, 2000 9 Phase III Trial of First-Line FOLFIRI/FOLFOX6 R A N D O M I Z E n=113 FOLFOX6* FOLFIRI† n=113 FOLFIRI FOLFOX6 Regimens: oxaliplatin* (100 mg/m2) or irinotecan† (180 mg/m2) IV + LV 200 mg/m2 over 2 hours d 1, 5-FU 2,400-3,000 mg/m2 over 46 hours Primary end point: TTP Secondary end points: ORR, safety Tournigand J Clin Oncol 22:229, 2004 10 Efficacy Arm A-FOLFIRI Arm B-FOLFOX P 1st line ORR (%) 56 54 NS 1st line PFS (mo) 8.5 8.0 .26 2nd PFS (mo) 14.2 10.9 .64 Overall Survival (mo) 21.5 20.6 .99 11 2007 A.S.C.O. Annual Meeting Chicago (USA), June 1-5 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. A. Falcone1,3, M. Andreuccetti1, I. Brunetti2, S. Ricci2, C. Barbara1, W. Evangelista4, V. Passeri5, S. Chiara6, G. Allegrini1, G. Masi1 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 FOLFOXIRI SCHEDULE CPT-11 165 mg/m2 Oxaliplatin 85 mg/m2 L-LV 200 mg/m2 1 hour 2 hours 5FU flat continuous infusion 3200mg/m2 48 hours Repeated every 14 days FOLFOXIRI vs. FOLFIRI: Summary Grade 3 diarrhea Grade 3 neutropenia Objective response rate (%) R0 surgery (%) Median OS (mo) FOLFOXIRI 20% 50% 60 15 23.6 FOLFIRI 12% 28% 34 6 16.7 p NA 0.0006 <0.001 0.033 0.042 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 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 ASCO 2007: XELOX-1 / NO16966 study design Recruitment June 2003 – May 2004 Recruitment Feb 2004 – Feb 2005 XELOX n=317 XELOX + placebo n=350 FOLFOX-4 n=317 FOLFOX-4 + placebo n=351 Initial 2-arm open-label study (n=634) XELOX + bevacizumab n=350 FOLFOX-4 + bevacizumab n=349 Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III data8 became available (n=1400) Courtesy Dr. Cassidy XELOX is non-inferior to FOLFOX-4 for Progression-Free Survival (intent-to-treat population) Cassidy, J. et al. J Clin Oncol; 26:2006-2012 2008 Copyright © American Society of Clinical Oncology Chemotherapy with or Without Bevacizumab: Efficacy Bev + chemorx Chemorx Hazard Ratio (p value) PFS (mo.) 9.4 8 0.83 (0.0023) PFS CapOX (mo.) 9.3 7.4 0.77 (0.0026) PFS FOLFOX4 (mo.) 9.4 8.6 0.89 (0.1871) OS (mo.) 21.3 19.9 0.89 (0.077) Saltz J Clin Oncol 26:2013, 2008 Yellow = significant White = not significant 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) 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 Courtesy Dr. Eric Van Cutsem PASCO 2007 *University Hospital Gasthuisberg, Leuven, Belgium CRYSTAL trial: Study design Cetuximab + FOLFIRI Untreated EGFR-expressing metastatic CRC Stratification factors: Regions ECOG PS Populations Randomized patients n=1217 Safety population n=1202 ITT population: n=1198 R Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks FOLFIRI irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks Courtesy Dr. Van Cutsem CRYSTAL Trial: Summary FOLFIRI FOLFIRI + Cetuximab Grade 3/4 Diarrhea (%) 10.5 15.2 Odds Ratio/HR (p value) -- Grade 3 Skin Toxicity (%) 0.2 18.7 -- ORR (%) 38.7 46.9 (0.0038) Median PFS (mo)* 8.0 8.9 RO Resection Rate (%) 1.5 4.3 0.851 (0.0479) 3 (0.0034) *Primary objective 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! 24 The Kitchen and Bathroom Sinks: “FOLFOXIRI” with Bev or Cetuximab •GI Symposium 2008: Phase II trial of FOLFOXIRI + bev in firstline 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 25 CAUTION! Emerging Concerns About Combining Chemotherapy and Two Biologics • PACCE1 (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-22 (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 VEGFdirected antibodies? • What about C80405 (current phase III Intergroup study)? 1GI Symp 2008 2ASCO 2008 26 SCHEDULING: CAIRO study CKTO 2002-07 Randomize Arm A Arm B capecitabine capecitabine + irinotecan 2nd line irinotecan capecitabine + oxaliplatin 3rd line capecitabine + oxaliplatin 1st line Courtesy Punt, PASCO 2007 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 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-21 suggested 7 month improvement in OS with use of maintenance chemotherapy instead of full holiday (p = 0.0545) 1ASCO 2007 29 Update on Systemic Therapy for Metastatic Colorectal Cancer: Conclusions After a 10-year explosion of new drugs, we have been bereft of new agents Questions still remain re: the optimal chemo- and biologic regimens in first and second-line settings More aggressive combinations seem to lead to greater downsizing of tumor -May equal greater rates of resectability and thus cure 30 Update on Systemic Therapy for Metastatic Colorectal Cancer: Conclusions (cont.) • Capecitabine may be substituted for 5FU, alone or in combination regimens • Don’t combine antibodies off study • The jury remains out on initial combinations versus sequential single-agent therapies • Selecting agents based on genetic testing is here (ras)! 31