Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147.

Abstract

3508 Background: FOLFOX is standard adjuvant therapy for resected stage III CC. N0147 assessed the potential benefit of Cmab added to FOLFOX in resected stage III CC. Initially N0147 enrolled pts regardless of KRAS status; here we report efficacy and toxicity results in mKRAS pts prior to an amendment requiring prospective KRAS testing. Methods: Pts were randomized to 12 biweekly courses of oxaliplatin 85 mg/m2 d1, with leucovorin 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 (mFOLFOX6), without (arm A) or with Cmab (arm D) 250 mg/m2 d1&8, with Cmab at 400 mg/m2, cycle 1, d1. Tumors were centrally tested for KRAS. This analysis focuses on pts with mKRAS CC. The primary endpoint was 3-yr disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Results: 658 pts with mKRAS CC were enrolled prior to the prospective collection of KRAS (Arm A, 340; Arm D, 318). Median follow-up is 22.4 months. 3-yr DFS favored FOLFOX alone (HR 1.48, 95% CI 1.08-2.03; p=0.02). No benefit of Cmab was observed in any of the subgroups assessed. OS also favored FOLFOX alone (HR 1.67, CI 1.00-2.80; p=0.07). Increased toxicity and greater differences in outcomes were observed in pts aged ≥ 70 (Table). Conclusions: The addition of Cmab to mFOLFOX6 resulted in impaired DFS and a trend toward impaired OS in mKRAS resected stage III CC pts. While some between-arm difference in toxicity and ability to complete the full course of FOLFOX were observed, it is unlikely these factors could account in whole for the poorer outcome with Cmab added to mFOLFOX6 in pts with mKRAS CC. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, aanofi-aventis, and Pfizer. Overall Age < 70 (n=566) Age >=70 (n=92) F F+C p F F+C p F F+C p 3-yr DFS 70.3 62.3 0.02 68.0 63.8 0.08 84.4 51.5 0.04 3-yr OS 86.1 79.1 0.07 85.9 81.8 0.20 88.0 65.4 0.10 On-study mortality 0.59 1.9 0.13 0.69 1.82 0.22 0 2.3 0.28 Any Gr ≥ 3 AE 52.7 68.9 <0.001 51.9 67.6 0.0002 57.1 76.7 0.05 Gr ≥ 3 diarrhea 7.5 14.8 0.003 6.7 13.1 0.01 12.2 25.6 0.10 Gr ≥ 4 neutropenia 11.1 12.9 0.48 9.5 13.1 0.18 20.4 11.6 0.26 Completed 12 cycles 73.7 68.0 0.11 74.8 68.5 0.10 66.7 65.1 0.88 Abbreviations: F, FOLFOX; F+C = FOLFOX + Cmab; p, p value. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Bristol-Myers Squibb, Celgene, Genentech, ImClone Systems, Pfizer, sanofi-aventis Bristol-Myers Squibb, sanofi-aventis Agensys, Amgen, Bristol-Myers Squibb, EMD Serono, Genentech, Idera, ImClone Systems, Lilly, Pfizer, Plexxikon, Roche, sanofi-aventis