Subgroup analyses results of the PETACC8 phase III trial comparing adjuvant FOLFOX4 with or without cetuximab (CTX) in resected stage III colon cancer (CC).

Abstract

3525^ Background: Potential benefit of adding CTX to the current standard treatment for stage III CC, was assessed. Subgroup analyses of demographic, clinical and molecular data may improve our understanding of this patient population. Methods: Patients (pts) were randomized 28-56 days following resection. They received 12 biweekly cycles of oxaliplatin 85 mg/m2 day (d) 1, with leucovorin 200 mg/m2, 5-FU 400 mg/m2 bolus IV, followed by 5-FU 600 mg/m2 22-hr IV on d1-2 (FOLFOX4), without (arm A) or with weekly CTX (arm B) 250 mg/m2 (initial dose 400 mg/m2). Primary endpoint was disease free survival time (DFS). Secondary endpoints included overall survival (OS), treatment compliance and safety. Enrolment was restricted to KRAS wt pts in 06/2008. Planned accrual of 1,407 KRAS wild-type (wt) pts provided 90% power to detect a hazard ratio (HR) of 0.75 with 2-sided α=0.05, with interim analyses after 65% of planned events. Preplanned subgroup analyses were performed. Results: 1,602 KRAS wt pts (811 arm A, 791 arm B) and 742 mutated (m) KRAS (prior to the amendment), were randomized. BRAF status was determined in 1134 (71%) KRAS wt pts. Median follow-up was 40 months. This interim analysis showed no difference between arms for DFS (HR 1.05, 95% CI 0.85-1.29; p=0.66) or OS (HR 1.09, 95% CI 0.81-1.47; p=0.55) in KRAS wt pts or for DFS (HR 0.99, 95% CI 0.75-1.28; p=0.91) or OS (HR 0.98, 95% CI 0.67-1.44; p=0.92) in KRAS/BRAF wt pts (n=984). Similar results were seen in KRAS mutant (mt) pts without any detrimental effect. In KRAS wt pts worse outcomes were seen with CTX in pts >70 years (n=149, DFS: HR 1.97, 95% CI 0.99-3.93; p=0.05), in females (n=666, HR 1.45, 95% CI 1.03-2.03; p=0.03) and in pts with right-sided CC (n=570, HR 1.40, 95% CI 1.01-1.94; p=0.04). Conversely, a better outcome was seen in pts with pT4pN2 CC (n=146, HR 0.55, 95% CI 0.35-0.89; p=0.01). Conclusions: Adding CTX to FOLFOX4 offered no benefit to pts with resected stage III KRAS wt, KRAS/BRAF wt and KRAS mt CC. Subgroup analyses suggest that KRAS wt pts with pT4pN2 tumors may derive benefit from CTX. MSI status determination is ongoing to explore its potential interaction with poor outcome in female and/or with right-sided tumors pts. Clinical trial information: NCT00265811.