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 mCRCYEAR 1ST LINE SALVAGE
1991 LV
1996, 1998 Irinotecan
2000 Irinotecan
2001 Capecitabine
2002 Oxaliplatin
2004 Oxaliplatin, Bevacizumab
Cetuximab
2006 Bevacizumab, Panitumumab
88
How Much Better Do We Do By Adding a New Drug: Summary Efficacy Data on Irinotecan + 5-
FU/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
99
How About Oxaliplatin: Summary Phase III Trial of First-Line 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
1010
Phase III Trial of First-Line FOLFIRI/FOLFOX6
FOLFOX6* FOLFIRI†
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: TTPSecondary end points: ORR, safety
n=113
n=113
Tournigand J Clin Oncol 22:229, 2004
RANDOMIZE
1111
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
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.
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. 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, GenovaITALY
FOLFOXIRI SCHEDULEFOLFOXIRI SCHEDULE
5FU flat continuous infusion3200mg/m2
L-LV 200 mg/m2
Oxaliplatin 85 mg/m2
2 hours
Repeated every 14 days
CPT-11165 mg/m2
48 hours1 hour
FOLFOXIRI vs. FOLFIRI: Summary
FOLFOXIRI FOLFIRI p
Grade 3 diarrhea 20% 12% NA
Grade 3 neutropenia 50% 28% 0.0006
Objective response rate (%) 60 34 <0.001
R0 surgery (%) 15 6 0.033
Median OS (mo) 23.6 16.7 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
XELOX + placebo n=350
FOLFOX-4 + placebo n=351
XELOX + bevacizumab
n=350FOLFOX-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 data8 became available (n=1400)
RecruitmentJune 2003 – May 2004
RecruitmentFeb 2004 – Feb 2005
ASCO 2007: XELOX-1 / NO16966 study design
Courtesy Dr. Cassidy
Copyright © American Society of Clinical Oncology
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)
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
*University Hospital Gasthuisberg, Leuven, Belgium
Courtesy Dr. Eric Van Cutsem PASCO 2007
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/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks
Cetuximab + FOLFIRI
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
RUntreated EGFR-expressing metastatic CRC
Courtesy Dr. Van Cutsem
CRYSTAL Trial: SummaryFOLFIRI FOLFIRI + Cetuximab Odds Ratio/HR
(p value)
Grade 3/4 Diarrhea (%) 10.5 15.2 --
Grade 3 Skin Toxicity (%) 0.2 18.7 --
ORR (%) 38.7 46.9 (0.0038)
Median PFS (mo)* 8.0 8.9 0.851
(0.0479)
RO Resection Rate (%) 1.5 4.3 3
(0.0034)
*Primary objective
2424
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!
2525
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
2626
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 VEGF-directed antibodies?
• What about C80405 (current phase III Intergroup study)?
1GI Symp 2008 2ASCO 2008
SCHEDULING: CAIRO study CKTO 2002-07
Arm A Arm B
Randomize
capecitabine
capecitabine +oxaliplatin
irinotecancapecitabine +
oxaliplatin
capecitabine +irinotecan1st line
2nd line
3rd 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
2929
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
3030
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
3131
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)!