Colorectal Cancer: What Next?
Neal J. Meropol, MD
Chief, Hematology and Oncology
University Hospitals Case Medical Center
Case Western Reserve University
January 18, 2014
For our consideration:
• Analysis of KRAS/NRAS mutations in the phase 3 20050181
study of panitumumab + FOLFIRI vs FOLFIRI as second-line
treatment for metastatic colorectal cancer (Peeters et al)
• Mutations within the EGFR signaling pathway: influence on
efficacy in FIRE-3 (Stintzing et al)
• Regular aspirin use improves survival in patients with PIK3CA
mutated metastatic colorectal cancer (Kothari et al)
• Maintenance treatment with capecitabine + bevacizumab
versus observation after induction treatment with
chemotherapy + bevacizumab in metastatic colorectal cancer
(Koopman et al)
Key Drivers in Colorectal Cancer
RAS
PI3K
RAF
Normanno et al. Nat Rev Clin Oncol, 2009
RAS Review
• Belongs to a superfamily
of GTPases
• Commonly mutated in
human cancer,
constitutive activation
• 3 members of the
subfamily: N, K, and H-ras
• Different expression
patterns and localization
in different tumors
• Functional differences not
fully delineated
Castellano and Santos. Genes and Cancer, 2011
RAS, RAF and PIK3CA Mutations in
Colorectal Cancer
• Mutation frequency
– KRAS: 40%
– NRAS: 3%
– BRAF: 5%
– PIK3CA: 15%
• BRAF and KRAS/NRAS
mutations are mutually
exclusive
• KRAS and NRAS
mutations are mutually
exclusive
De Roock, Lancet Oncol, 2010
EGFR Antibodies in Colorectal Cancer
• 2004 - Regulatory approval initially required
EGFR expression by IHC
• 2009 - ASCO Provisional Clinical Opinion: do
not administer anti-EGFR antibodies to
patients with tumors that harbor codon 12/13
KRAS mutations (Allegra et al. JCO, 2009)
Next Question: What about RAS family
mutations other than exon 2 in KRAS?
Datasets
PRIME: FOLFOX +/-panitumumab
(Doulliard, NEJM 2013)
FIRE-3: FOLFIRI + cetuximab or
bevacizumab (Stintzing, GI Symp 2014)
20050181: FOLFIRI +/- panitumumab
(Peeters, GI Symp 2014 2014)
First-line
First-line
Secondline
Reminder – A prospective randomized
clinical trial is the gold standard. A
prospective-retrospective study may be
adequate if:
• a priori hypothesis and statistical design
• biomarker assay validated
• samples available from vast majority of
patients
• adequate follow up and annotation
PRIME Study: FOLFOX +/- Pmab
First-Line
PFS
Exon 2 WTOther Mut
OS
Exon 2 WTOther Mut
Douillard J et al. N Engl J Med 2013;369:1023-1034.
20050181: FOLFIRI +/- Pmab
Second-Line
Favors Pmab Favors FOLFIRI Alone
N
HR
WT KRAS Exon 2
MT KRAS Exon 2
WT RAS
MT RAS
WT KRAS Exon 2 MT RAS
Unevaluable RAS
597
486
415
593
107
178
0.73
0.85
0.70
0.86
0.89
0.85
0.59
0.68
0.54
0.70
0.56
0.57
-0.90
-1.06
-0.90
-1.05
-1.42
-1.25
WT KRAS Exon 2
MT KRAS Exon 2
WT RAS
MT RAS
WT KRAS Exon 2 MT RAS
Unevaluable RAS
597
486
415
593
107
178
0.85
0.94
0.80
0.91
0.83
1.01
0.70
0.76
0.63
0.76
0.53
0.71
-1.04
-1.15
-1.02
-1.10
-1.29
-1.45
Efficacy Analysis Sets
PFS
OS
0.10
1.00
95%CI
10.00
Hazard Ratio (Pmab+FOLFIRI / FOLFIRI Alone)
• PFS benefit of Pmab restricted to RAS WT population
• RR benefit of Pmab restricted to RAS WT population
Peeters et al. GI Symp 2014
FIRE-3 Study: FOLFIRI + cetuximab or
bevacizumab first-line
• Favor bevacizumab
– Improved PFS and response rate (trend) RAS
mutant
– Trend toward improved PFS (but not OS) with
PIK3CA mutant
• Favor cetuximab
– Improved OS (but not PFS) with RAS wt (7.5
month improvement)
What have we learned?
• RAS mutations beyond exon 2 are common (15-18%)
• Patients with any RAS mutations do not appear to benefit
(at least no major benefit) from anti-EGFR treatment
• Among patients with no RAS mutations, a clinically
meaningful survival benefit is observed with cetux vs
bevacizumab (but no difference in PFS)
– Results of Alliance 80405 are eagerly awaited!
• Currently, incomplete data regarding potential biologic
differences when combining EGFR inhibitors with different
chemotherapy backbones, and between different RAS
mutations
• A pooled analysis of ALL available studies is encouraged!
Aspirin and PIK3CA
PIK3CA, Prostaglandins, and Colon Cancer
PIK3CA activating mutations
are present in 15-20% of
colorectal cancers
Complex interactions exist
between PI3K , other
signaling pathways, and
prostaglandin synthesis
which contribute to
development and growth of
colorectal cancer
Markowitz SD. N Engl J Med 2007
Does PIK3CA mutational
status influence the
response to aspirin?
Aspirin’s affects extend well beyond tumor
intracellular signalling
Fuchs C S , and Ogino S JCO 2013;31:4358-4361
964 Participants in the Nurses’ Health Study and the
Health Professionals Follow-up Study with Colorectal
Cancer
Superior colorectal
cancer-specific
survival (HR=0.18,
p<0.001) and
overall survival
(HR=0.54 , P=0.01)
with regular aspirin
use in PIK3CA
mutants
Liao X, et al. N Engl J Med. 2012;367: 1596-606.
VICTOR Trial: Adjuvant Study of Rofecoxib vs.
Placebo (N=896; 12% PIK3CA mutant)
WT
Mutant
RFS
OS
Domingo E et al. JCO 2013;31:4297-4305
No greater benefit of
rofecoxib based on
PIK3CA mutation status
Regular aspirin use
(14%) associated with
reduced rate of
recurrence in patients
with PIK3CA-mutant
cancers (HR, 0.11; P
.027; but not in patients
lacking tumor PIK3CA
mutation (HR, 0.92; P
.71).
Aspirin in PIK3CA Colorectal Cancer
(Kothari et al. GI Symp 2014)
•
•
•
•
Convenience sample of 185 patients
49 reported aspirin use
Stage distribution: 1/2/3/4  8/66/67/44
No clear overall survival benefit among ASA
users; trend towards benefit in stage 4
Do the “negative” data provided by Kothari et al
refute the underlying hypothesis? NO.
•
•
•
•
•
•
Challenges with current datasets
No randomization between ASA and no ASA
Reliance on patient reporting of ASA use
Variation in dosing among ASA users
Mix of stages included
Small sample sizes of PIK3CA mutants
Potential unmeasured variables that could impact
ASA – PIK3CA relationship, including other
treatments received
Prospective evaluation of ASA and
COX-2 inhibition in PIK3CA mutant CRC
is needed
Ongoing/Planned randomized trials of
ASA and celecoxib in the adjuvant
setting will provide meaningful data
Is maintenance therapy superior to “treatment
holiday” after induction? CAIRO3 (Koopman et al)
• N=558, <20% prior adjuvant treatment; ~60% had
resection of primary tumor
• Only 60% of patients in obs arm restarted CAPOX-B;
most received some treatment
• PFS favors maintenance (HR=.67, p <.0001 ; PFS2 8.5
vs. 11. 7 mo) BUT no clear difference in overall
survival (multivariate analysis suggests benefit of M)
• Patients who achieve initial response or have primary
tumor removed (in case of synchronous metastasis)
may have improved survival with maintenance
What have we learned from
CAIRO3?
• It is feasible yet challenging to conduct a
“window of opportunity” study after
induction (<2 patients per center per year)
• Maintenance treatment clearly will delay
progression
• More work is needed to identify those
patients who may safely receive a “treatment
holiday”
Patient Survival
Colorectal Cancer S-Curve
More Tweaking
New Cytotoxics and Antibodies
Tweaking 5-FU
1980s
1990s
2000s
Era
Patient Survival
We must jump to the next curve
Era
How to get there
Technology
Teamwork
Trials
Genomics
Big data
Public-Private
Biobanking
Acknowledge that all cancers will be rare
diseases
-New clinical trials models
-New infrastructure and regulatory models