Transcript Can Society Afford State-of-the

Systemic Treatment of Metastatic
Colorectal Cancer: Living with a
Moving Landscape
Neal J. Meropol, MD
Fox Chase Cancer Center
May 16, 2005
History of Systemic Therapy for
Colorectal Cancer
Patient Benefit
?
5-FU Modulation
Biologics
New Cytotoxics
1980’s
1990’s
2000’s
bevacizumab
5-FU/leucovorin
capecitabine
oxaliplatin
cetuximab
capecitabine/irinotecan
irinotecan
FOLFIRI
IFL
FOLFOX
cetuximab/irinotecan
capecitabine/oxaliplatin
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 5FU/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
Treatment Summary: 2nd-, 3rd-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
Survival with Metastatic Colorectal Cancer:
Chemotherapy
With
antibodies?
FOLFOX
FOLFIRI
IROX
IFL
Grothey, A. et al. J Clin Oncol; 22:1209-1214 2004
Some Practical Clinical
Questions
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Capecitabine combinations?
Optimal second line?
Combinations of biologics?
Cetuximab front-line?
Cetuximab before irinotecan failure?
Non-irinotecan cetuximab combinations?
Bevacizumab for life?
Questions Addressed Today
• Capecitabine combinations?
• Optimal second line?
• Combinations of biologics?
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
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)
CAPOX vs. FUFOX Overall Survival
Estimated probability
1.0
CAPOX (n=238)
FUFOX (n=230)
0.8
Median
16.3 months
17.2 months
HR = 1.05 (95% CI: 0.79–1.41)
p=0.72 (Log-rank)
0.6
0.4
0.2
0
0
20
40
60
80
Weeks
100
120
140
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
N9841 Results
• Equivalent overall survival, 14.7 (I) vs. 13.5
(FOLFOX) months (HR=1.05, 95% CI 0.91.3)
• 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)
N9841: Overall Survival
100
90
80
% Alive
70
60
50
40
30
CPT-11
20
N = 245
FOLFOX
10
N = 246
0
0
2
4
6
8
10 12
14 16
18 20
Months from Registration
22 24
Randomized phase II trial of
cetuximab/bevacizumab/irinotecan (CBI)
versus cetuximab/bevacizumab (CB) in
irinotecan-refractory colorectal cancer
Saltz et al. ASCO 2005, #3508
EGFR Antibodies Block Ligand
Binding and Downstream Signaling
Antibody
Pao, W. et al. J Clin Oncol; 23:2556-2568 2005
Rational Combinations
EGFR and
VEGF
Inhibitors
VEGF
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
Rational Combinations
EGFR + IGF-1R or
HER2 Inhibitors
EGFR and
AKT/mTOR
Inhibitors
EGFR and
RAS/Raf/MEK/
MAPK
Inhibitors
What have we learned?
1.
2.
3.
For many patients, metastatic colorectal cancer
is no longer an acute illness
There is more than one correct way to use
drugs with modest activity in unselected
populations
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
The Big Questions that Should
Guide Future Clinical
Research:
How do these drugs work and
who should get them?
Matchmaking is Science
Potential Sources of Variability
• The tumor
– Target characteristics
– Target relevance
– Drug disposition
– Resistance mechanisms
• The patient
– Drug metabolism
– Normal tissue sensitivity
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
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