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*: Coordinating group

Phase III Clinical Trial of FOLFOX with or without Cetuximab in Resected K-ras wild type Stage 3 Colon Cancer: Cooperative Group Trial N0147 (NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG).

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*: Coordinating group

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  1. Phase III Clinical Trial of FOLFOX with or without Cetuximab in Resected K-ras wild type Stage 3 Colon Cancer: Cooperative Group Trial N0147(NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG) Steven Alberts, DanielSargent, Thomas Smyrk, Anthony Shields, Emily Chan, Richard Goldberg, Sharlene Gill, Morton Kahlenberg, Stephen Thibodeau, Suresh Nair *: Coordinating group

  2. Disclosures NCI provided primary support for the trial Additional grants to support the trial and its translational components received from: • Bristol-Myers Squibb • ImClone Systems • wholly-owned subsidiary of Eli Lilly and Company • sanofi-aventis • Pfizer

  3. Background: Adjuvant Standard • Combination of 5-FU, Oxaliplatin, and LV establish as the standard of adjuvant therapy for resected stage 3 colon cancer • MOSAICFOLFOX4 versus LV5FU2 • NSABP C-07FLOX versus 5-FU/LV 3-year Disease Free Survival: ≈70%

  4. Potential Added Benefit of Targeted Therapy • Limitation of new chemotherapy drugs to improve outcomes • Monoclonal antibodies against EGFR and VEGF demonstrate improved outcome in metastatic colorectal cancer when combined with chemotherapy

  5. Initial 2-arm Design for N0147 • mFOLFOX6 (12 cycles) • Oxaliplatin 85 mg/m2 • LV 400 mg/m2 & • 5-FU 2,400 mg/m2 over 46 hrs • every 2 weeks R A N D O M I Z E Stage 3 Colon Cancer (N = 2300) • mFOLFOX6 + Cetuximab • (12 cycles) • mFOLFOX6 • Cetuximab days 1,8 • - 400 mg/m2 loading dose • - 250 mg/m2 weekly

  6. Role of K-ras Analysis • Ability to select patients based on K-ras status established in early 2008 • Mutated K-ras (K-ras Mut) predicts for lack of response to cetuximab • Wild type K-ras (K-ras WT) maintain ability to respond to cetuximab

  7. Report of K-ras Results (Bokemeyer et al, JCO 2009)

  8. Final Design for N0147 – June 2008 R A N D O M I Z E Arm A mFOLFOX6 P R E R E G I S T E R K-ras WT Arm D mFOLFOX6 + Cetuximab Stage 3 Colon Cancer (N = 3768) Centralized K-ras analysis R E G I S T E R • Arm G • Adjuvant therapy per primary oncologist • Report therapy given • Annual status through year 8 K-ras Mut

  9. K-ras Assessment • K-ras Testing: • Centralized testing performed in a CLIA approved lab at Mayo Clinic • DxS Assay using the Roche LightCycler 480 platform • 99.2% of samples provided interpretable result

  10. Goals for N0147 • Primary • Compare disease free survival (DFS)between mFOLFOX6 and mFOLFOX6 + cetuximab in patients withK-ras WT • Secondary • Compare overall survivalin the two groups • Assesstoxicitiesresulting from the addition of cetuximab

  11. N0147 Analysis plan • Sample size: 2070 K-ras WT patients to provide 515 DFS events • 90% power to detect HR of 1.33 (based on assumed 3 yr DFS on FOLFOX of 70%, two-sided test, level 0.05) • Intent-to-treat analysis • Protocol specified interim analyses after 25%, 50%, and 75% of events

  12. Eligibility for N0147 • Inclusion • Completely resected colon adenocarcinoma • > 1 pathologically confirmed lymph node identified • Age > 18 years • Acceptable liver and kidney function • Standard hematologic parameters

  13. Eligibility for N0147 • Exclusion • Evidence of metastatic disease • En bloc resection for locally advanced disease allowed • Rectal cancer • Prior chemotherapy or radiation for colon cancer • Prior or concurrent malignancies within 5 years • Clinically significant peripheral neuropathy

  14. Final Study Population • 2967 patients from 478 sites accrued to arms A, D, and G • 62% K-ras WT • 1864 randomized to A (FOLFOX) or D (FOLFOX + cetuximab) • Trial halted on findings of planned interim analysis • 90% of planned accrual • Median follow-up 23 months

  15. Outcomes for K-ras WT Patients

  16. Disease Free Survival (N=1847)

  17. Disease Free SurvivalAge<70 (N=1589)

  18. Disease Free SurvivalAge>70 (N=258)

  19. Overall Survival (N=1847)

  20. Forest Plot for DFS Favors FOLFOX alone

  21. Toxicity – Grade 3-4

  22. Reasons for Discontinuation

  23. Conclusions • No benefit to adding cetuximab in patients with resected stage 3 K-ras WT expressing colon cancer • Potential explanations • Decreased tolerance with cetuximab • Differences in dose intensity • Interaction with age: • Worse outcomes in older patients receiving cetuximab • Lessened ability to complete therapy

  24. Conclusions • Mechanistic • Cetuximab may have a different form of activity on micrometastatic disease compared to that observed in stage 4 disease • Differences in biology of earlier stage disease • Current focus of correlative studies

  25. Acknowledgments • Special thanks to all of the participating patients • Collaborative North American effort • Trial not possible without the support of NCI and that provided by Bristol-Myers Squibb, sanofi-aventis, ImClone, and Pfizer • Study Team

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