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Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutant resected stage III colon cancer. Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven Alberts.
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Adjuvant mFOLFOX6 +/- cetuximab in patients with K-ras mutantresected stage III colon cancer Richard Goldberg, Daniel Sargent, Stephen Thibodeau, Michelle Mahoney, Anthony Shields, Emily Chan, Sharlene Gill, Morton Kahlenberg, Suresh Nair, Steven Alberts Cooperative Group Trial N0147NCCTG*, CALGB, ECOG, NCIC, NSABP, SWOG * Coordinating group
Disclosures Dr Goldberg has received honoraria, consulting fees or research support from Bristol Meyers Squibb ImClone sanofi-aventis
EGF Receptor: Its Role in CRC Therapy Venook, Oncologist 2005 pY PI3K pY pY pY PTEN STAT AKT Ligand Antibodies to EGFRcetuximab, panitumumab RAS RAF EGFR-TK MEK MAPK Gene transcription Cell-cycle progression Proliferation Survival (anti-apoptosis) Chemotherapy /radiotherapy resistance Invasion and metastasis Angiogenesis
EGF Receptor: Venook, Oncologist 2005 pY PI3K pY pY pY PTEN STAT AKT Ligand RAS RAF EGFR-TK MEK MAPK Gene transcription Cell-cycle progression Proliferation Survival (anti-apoptosis) Chemotherapy /radiotherapy resistance Invasion and metastasis Angiogenesis
EGF Receptor: Venook, Oncologist 2005 pY PI3K pY pY pY PTEN STAT AKT Ligand RAS RAF EGFR-TK MEK MAPK Gene transcription Cell-cycle progression Proliferation Survival (anti-apoptosis) Chemotherapy /radiotherapy resistance Invasion and metastasis Angiogenesis
Clin Ca Res, Jan 2005 “Bypass” Pathways and EGFR Resistance
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
DFS: FOLFOX +/- Cmab by K-ras status K-Ras WT K-Ras Mut
OS: FOLFOX +/- Cmab by K-ras status K-Ras WT K-RasMut
Duration of Therapy K-Ras WT K-Ras Mut
Was adverse impact of Cetuximab due to dosing issues? In post-hoc analysis, attempted to identify ‘ideal’ patients First 6 cycles with > 80% dose intensity for all drugs Consider only patients aged < 70 If no benefit in these pts (young, > 80% dose rec’d), then adverse impact not likely due to reduced dosing
Was adverse impact of Cetuximab due to dosing issues? Comparison based on dosing not protected by randomization, thus possibly confounded with other reasons for stopping treatment Alternative Use Time to Recurrence endpoint Most sensitive Least confounded
Dose Intensity (% with > 80%) K-ras WT Cycle 6 Cycle 10
Dose Intensity (% with > 80%) K-rasMut Cycle 6 Cycle 10
“Idealized” Patient Comparison: Time to Recurrence – K-Ras WT All Patients “Ideal” Patients
“Idealized” Patient Comparison: Time to Recurrence – K-Ras Mut All Patients “Ideal” Patients
Time to Recurrence: FOLFOX +/- Cmab in K-Ras WT Age < 70 Age > 70
Time to Recurrence: FOLFOX +/- Cmab in K-Ras Mut Age < 70 Age > 70
% Grade 3+ Adverse Events K-Ras WT K-Ras Mut AEs did not differ by KRAS status
Why did patients with K-rasMut treated with Cetuximab do worse? • While they had lower drug exposure, we don’t believe that is the key reason based on the idealized patient analysis • We believe that the explanation is related to tumor biology • Hypothesis: Cetuximab treatment of K-ras mutated tumors drives chemotherapy resistance
Conclusion • The outcomes are surprising • Understanding the interactions of tumor genotype and patient biology challenge us. • The key to individualizing care lies in that understanding. • We hope to find the answers in the tumor blocks