Background
FIRE-3 was a randomized, open-label phase III trial in 592 patients with KRAS exon 2 (codon 12/13) wild-type metastatic colorectal cancer and no prior therapy for metastatic disease. Compared first-line FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. Final survival/per-protocol analysis reported by Heinemann V et al, BJC 2020 (PMID: 33154570).
Interventions and follow up
Arm A: Cetuximab (400 mg/m2 over 120 min C1, then 250 mg/m2 over 60 min) plus FOLFIRI (irinotecan 180 mg/m2, LV 400 mg/m2, 5-FU 400 mg/m2 bolus then 2400 mg/m2 46-h infusion) every 2 weeks
Arm B: Bevacizumab 5 mg/kg plus FOLFIRI every 2 weeks
Primary endpoint: Objective response rate (ORR)
Median follow-up: 71 mo vs 76 mo, arm A vs arm B (final analysis)
Arm B: Bevacizumab 5 mg/kg plus FOLFIRI every 2 weeks
Primary endpoint: Objective response rate (ORR)
Median follow-up: 71 mo vs 76 mo, arm A vs arm B (final analysis)
Results
ORR (primary, ITT KRAS wt): 66% vs 59% (OR 1.36, 95% CI 0.90-2.03, P=.15) — not significant
Median OS (KRAS wt): 33 mo vs 26 mo (HR 0.75, 95% CI 0.59-0.94, P=.011)
Median OS, left-sided primary: 38 mo vs 28 mo (HR 0.71, 95% CI 0.55-0.92, P=.01)
Median OS, right-sided primary: 19 mo vs 23 mo (HR 1.14, 95% CI 0.71-1.84, P=.60)
Median OS (KRAS wt): 33 mo vs 26 mo (HR 0.75, 95% CI 0.59-0.94, P=.011)
Median OS, left-sided primary: 38 mo vs 28 mo (HR 0.71, 95% CI 0.55-0.92, P=.01)
Median OS, right-sided primary: 19 mo vs 23 mo (HR 1.14, 95% CI 0.71-1.84, P=.60)
Adverse events
Overall (grade ≥3): 64% vs 51%, arm A vs arm B; 5 deaths from serious AEs in arm B vs none in arm A
Cetuximab-specific (any grade): Acneiform exanthema 78%, paronychia 38%, skin desquamation 37%
Bevacizumab-specific (grade ≥3): Hypertension 37%, bleeding 30%, thromboembolic events 18%
Cetuximab-specific (any grade): Acneiform exanthema 78%, paronychia 38%, skin desquamation 37%
Bevacizumab-specific (grade ≥3): Hypertension 37%, bleeding 30%, thromboembolic events 18%
Conclusions
Although the primary ORR endpoint was not met, FOLFIRI plus cetuximab significantly improved overall survival over FOLFIRI plus bevacizumab in KRAS wild-type mCRC, with benefit concentrated in left-sided primary tumors.
Key Limitations
Primary endpoint (ORR) was negative; OS benefit was a secondary endpoint and the open-label design risks bias. Sidedness and extended-RAS analyses were retrospective/subgroup-derived. Originally enrolled on KRAS exon 2 alone, before extended-RAS testing became standard.
Clinical Context
FIRE-3, together with CALGB/SWOG 80405, established primary tumor sidedness as a key determinant of anti-EGFR benefit. ESMO guidelines recommend anti-EGFR therapy (cetuximab or panitumumab) with chemotherapy as preferred first-line for RAS wild-type, left-sided mCRC; bevacizumab is favored for right-sided tumors.
References
Heinemann V et al, BJC, 2020 (final analysis), PMID: 33154570; original Heinemann V et al, Lancet Oncol, 2014, PMID: 25088940