Background
Phase III randomized trial in 1137 patients with previously untreated KRAS wild-type advanced/metastatic colorectal cancer. Compared first-line chemotherapy backbone (mFOLFOX6 or FOLFIRI, investigator choice) combined with cetuximab versus bevacizumab. Patients with CNS metastases or significant GI bleeding/perforation excluded.
Interventions and follow up
Arm A: mFOLFOX6 or FOLFIRI plus cetuximab (400 mg/m2 over 120 min C1, 250 mg/m2 subsequent) every 2 weeks
Arm B: mFOLFOX6 or FOLFIRI plus bevacizumab (5 mg/kg) every 2 weeks
Primary endpoint: Overall survival
Median follow-up: 47.4 mo
Arm B: mFOLFOX6 or FOLFIRI plus bevacizumab (5 mg/kg) every 2 weeks
Primary endpoint: Overall survival
Median follow-up: 47.4 mo
Results
Median OS (overall): 30.0 mo vs 29.0 mo, cetuximab vs bevacizumab (HR 0.88, 95% CI 0.77-1.01, P=.09) — not significant
Median PFS: 10.5 mo vs 10.6 mo (no significant difference)
Left-sided primary OS (post-hoc): longer with cetuximab; right-sided OS longer with bevacizumab
Median PFS: 10.5 mo vs 10.6 mo (no significant difference)
Left-sided primary OS (post-hoc): longer with cetuximab; right-sided OS longer with bevacizumab
Adverse events
Cetuximab arm: Predominant grade ≥3 toxicity acneiform/skin rash; hypomagnesemia
Bevacizumab arm: Predominant grade ≥3 toxicity hypertension
Overall: Rates of AEs occurring in ≥10% of patients were broadly similar between arms
Bevacizumab arm: Predominant grade ≥3 toxicity hypertension
Overall: Rates of AEs occurring in ≥10% of patients were broadly similar between arms
Conclusions
In KRAS wild-type advanced colorectal cancer, first-line cetuximab and bevacizumab combined with chemotherapy produced no significant difference in overall survival; subsequent sidedness analyses showed differential benefit by primary tumor location.
Key Limitations
Enrolled on KRAS exon 2 testing only; extended-RAS and sidedness analyses were retrospective/post-hoc. Mixed chemotherapy backbones (FOLFOX or FOLFIRI) introduce heterogeneity. Open-label design.
Clinical Context
CALGB/SWOG 80405, with FIRE-3, drove the shift toward selecting biologics by primary tumor sidedness. ESMO guidelines recommend anti-EGFR plus chemotherapy as preferred first-line for RAS wild-type left-sided mCRC, and bevacizumab-based therapy for right-sided tumors.