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Advances in Colorectal Cancer: Exploring RAS and PIK3CA Mutations Impact on Treatment

This presentation by Dr. Neal J. Meropol discusses key findings in colorectal cancer research, especially focusing on KRAS/NRAS mutations and their influence on treatment efficacy. It highlights the importance of genetic profiling, the effects of regular aspirin use in patients with PIK3CA mutations, and results from several pivotal studies regarding treatment combinations like panitumumab with FOLFIRI. The analysis includes insights into the significance of RAS mutations and the need for further prospective studies in improving patient outcomes.

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Advances in Colorectal Cancer: Exploring RAS and PIK3CA Mutations Impact on Treatment

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  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

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