Colorectal Cancer: What Next?

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 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)

3. Key Drivers in Colorectal Cancer RAS PI3K RAF Normannoet al. Nat Rev ClinOncol, 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 • 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)

7. Next Question: What about RAS family mutations other than exon 2 in KRAS?

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 +/- PmabFirst-Line PFS Exon 2 WT- Other Mut OS Exon 2 WT- Other Mut Douillard J et al. N Engl J Med 2013;369:1023-1034.

10. 20050181: FOLFIRI +/- PmabSecond-Line Favors Pmab Favors FOLFIRI Alone N HR 95%CI Efficacy Analysis Sets WT KRAS Exon 2 597 0.73 0.59 -0.90 PFS MT KRASExon 2 486 0.85 0.68 -1.06 WT RAS 415 0.70 0.54 -0.90 MT RAS 593 0.86 0.70 -1.05 WT KRASExon 2 MT RAS 107 0.89 0.56 -1.42 UnevaluableRAS 178 0.85 0.57 -1.25 OS WT KRAS Exon 2 597 0.85 0.70 -1.04 MT KRASExon 2 486 0.94 0.76 -1.15 WT RAS 415 0.80 0.63 -1.02 MT RAS 593 0.91 0.76 -1.10 WT KRASExon 2 MT RAS 107 0.83 0.53 -1.29 UnevaluableRAS 178 1.01 0.71 -1.45 0.10 1.00 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

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 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!

13. Aspirin and PIK3CA

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;31:4358-4361

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: 1596-606.

17. 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). Mutant WT RFS OS Domingo E et al. JCO 2013;31:4297-4305

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. 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 neededOngoing/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? 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

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