FOLFIRI PLUS Bev in mCRC

Background

Phase III randomized, double-blind trial in 813 patients with previously untreated metastatic colorectal cancer. Tested whether adding bevacizumab to first-line bolus IFL (irinotecan/5-FU/leucovorin) chemotherapy improves overall survival.

Interventions and follow up

Arm A: IFL (irinotecan 125 mg/m2, 5-FU 500 mg/m2, leucovorin 20 mg/m2) D1, D8, D15, D22 plus bevacizumab 5 mg/kg D1, D15 every 6 weeks
Arm B: IFL plus placebo D1, D15 every 6 weeks
Primary endpoint: Overall survival
Follow-up: NR

Results

Median OS: 20.3 mo vs 15.6 mo, IFL+bevacizumab vs IFL+placebo (HR 0.66, P<.001)
Median PFS: 10.6 mo vs 6.2 mo (HR 0.54, P<.001)
Objective response rate: 44.8% vs 34.8% (P=.004)

Adverse events

Overall (grade ≥3): 84.9% vs 74.0%, arm A vs arm B
Vascular: Grade 3 hypertension 11.0% vs 2.3%; any thromboembolic event 19.4% vs 16.2%; GI perforation 1.5% (arm A only)
GI/hematologic: Diarrhea 32.4% vs 24.7%, leukopenia 37.0% vs 31.0%

Conclusions

Adding bevacizumab to IFL chemotherapy significantly improved overall survival, progression-free survival, and response rate in metastatic colorectal cancer, establishing antiangiogenic therapy as a first-line standard.

Key Limitations

The IFL chemotherapy backbone is now obsolete, superseded by FOLFOX/FOLFIRI, limiting direct applicability. No predictive biomarker for bevacizumab benefit identified. Bevacizumab carries risks of bleeding, hypertension, thromboembolism, and rare GI perforation.

Clinical Context

This pivotal trial led to FDA approval of bevacizumab for first-line mCRC in 2004, the first antiangiogenic agent approved in oncology. ESMO guidelines support bevacizumab plus doublet chemotherapy as a first-line option, particularly for right-sided or RAS-mutant tumors where anti-EGFR therapy is not indicated.

References