Phase II Trial of FOLFOX6, Bevacizumab, and Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer

Abstract: Purpose: To examine FOLFOX/bevacizumab/cetuximab in the first-line treatment of metastatic colorectal cancer (mCRC). Methods: Design: Randomized phase II trial aimed at achieving a 60% objective response rate (ORR). Due to frequent cetuximab-related hypersensitivity reactions the trial was amended to a single-arm design. Eligibility: Previously untreated mCRC, measurable disease, Eastern Cooperative Oncology Group performance status (ECOG-PS) 0–1. Treatment: Modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 350 mg, and 5-fluorouracil 400 mg/m2 bolus; 2.4 g/m2 infusion, 46 h) day 1; bevacizumab 5 mg/kg on day 1; cetuximab 400 mg/m2 on day 1, then 250 mg/m2 on days 1 and 8, every 14 days (1 cycle) until progressive disease (PD); restaging occurred every 4 cycles. Results: With emerging negative progression-free survival (PFS) data from a similarly designed trial, this trial closed early. Enrollment (N=31) was from August 2005–June 2008. Patient characteristics: Median age was 55 years (29–78); 58% were male; 71% were ECOG-PS 0. Ten cycles (median) were completed (range 2–62). The ORR was 55% (95% confidence interval [CI], 36–73%); 11 patients (35%) had stable disease; 1 patient (3%) had PD; 2 patients (6%) were unevaluable. Median PFS was 9 months (95% CI, 8.3–15.2 months); median overall survival was 25.7 months (95% CI, 15.4–27.6 months). Grade 3/4 toxicities (>1 patient) included neutropenia (25%), rash (23%; grade 2 events, 45%), diarrhea (19%), fatigue (16%), pain (16%), anemia (13%), sensory neuropathy (13%), deep-vein thrombosis (10%), nausea (10%), pulmonary embolism (7%), anorexia (6%), and vomiting (6%). Conclusion: In this limited trial, it is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab’s role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials.