1. Colorectal Cancer: What Next?
Neal J. Meropol, MD
Chief, Hematology and Oncology
University Hospitals Case Medical Center
Case Western Reserve University
January 18, 2014

2. For our consideration:
Analysis of KRAS/NRAS mutations in the phase 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)

3. Key Drivers in Colorectal Cancer
RAS
RAF
PI3K
Normanno et al. Nat Rev Clin Oncol, 2009

4. 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

5. 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

6. EGFR Antibodies in Colorectal Cancer
Regulatory approval initially required EGFR expression by IHC
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)

7. Next Question: What about RAS family mutations other than exon 2 in KRAS?
Datasets
PRIME: FOLFOX +/-panitumumab (Doulliard, NEJM 2013)
First-line
FIRE-3: FOLFIRI + cetuximab or bevacizumab (Stintzing, GI Symp 2014)
: FOLFIRI +/- panitumumab (Peeters, GI Symp )
Second-line

8. 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

9. PRIME Study: FOLFOX +/- Pmab First-Line
PFS
Exon 2 WT-
Other Mut OS
Exon 2 WT-
Other Mut
Douillard J et al. N Engl J Med 2013;369:

10. 20050181: FOLFIRI +/- Pmab Second-Line
0.10
1.00
10.00
WT KRAS Exon 2
MT KRAS Exon 2
WT RAS
MT RAS
WT KRAS Exon 2 MT RAS
Efficacy Analysis Sets
N HR %CI
Favors Pmab
Favors FOLFIRI Alone
Hazard Ratio (Pmab+FOLFIRI / FOLFIRI Alone)
Unevaluable RAS
PFS OS
PFS benefit of Pmab restricted to RAS WT population
RR benefit of Pmab restricted to RAS WT population
Peeters et al. GI Symp 2014

11. 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)

12. 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 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!

13. Aspirin and PIK3CA
P100 alpha catalytic subunit

14. 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
Does PIK3CA mutational status influence the response to aspirin?
Markowitz SD. N Engl J Med 2007

15. Aspirin’s affects extend well beyond tumor intracellular signalling
Fuchs C S , and Ogino S JCO 2013;31:

16. 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:

17. VICTOR Trial: Adjuvant Study of Rofecoxib vs
VICTOR Trial: Adjuvant Study of Rofecoxib vs. Placebo (N=896; 12% PIK3CA mutant)
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). WT
Mutant
RFS OS
Domingo E et al. JCO 2013;31:

18. 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

19. Challenges with current datasets
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

20. 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

21. Is maintenance therapy superior to “treatment holiday” after induction
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 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

22. 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”

23. Colorectal Cancer S-Curve
More Tweaking
Patient Survival
New Cytotoxics and Antibodies
Tweaking 5-FU
1980s 1990s 2000s
Era

24. We must jump to the next curve
Patient Survival
Era

25. How to get there Genomics Big data Technology Public-Private
Biobanking
Teamwork
Acknowledge that all cancers will be rare diseases
-New clinical trials models
-New infrastructure and regulatory models
Trials