Download Update on Systemic Therapy for Metastatic Colorectal Cancer

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
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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
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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!
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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
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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
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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
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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)!
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