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*: Coordinating group

This phase III clinical trial examines the efficacy of FOLFOX with or without Cetuximab in resected K-ras wild-type stage 3 colon cancer. The trial involves a comparison of disease-free survival and overall survival between the two treatment groups, assessing toxicities and treatment outcomes. The study, supported by NCI and various grants, aims to determine the impact of adding Cetuximab to standard adjuvant therapy in K-ras wild-type patients. The results indicate no added benefit of Cetuximab in this patient population, highlighting potential factors influencing treatment outcomes.

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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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