Background
FIRE-4.5 (AIO KRK-0116): randomized, open-label phase 2 trial. 107 patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC), randomized 2:1 (arm A n=72, arm B n=35). Tested FOLFOXIRI plus cetuximab vs bevacizumab.
Interventions and follow up
Arm A: FOLFOXIRI + cetuximab Q2W
Arm B: FOLFOXIRI + bevacizumab Q2W
Primary endpoint: Objective response rate (ORR)
Median follow-up: NR
Arm B: FOLFOXIRI + bevacizumab Q2W
Primary endpoint: Objective response rate (ORR)
Median follow-up: NR
Results
ORR: 49.2% (cetuximab, arm A) vs 60.0% (bevacizumab, arm B); did not meet primary endpoint
mPFS: 8.3 mo (cetuximab) vs 5.9 mo (bevacizumab); HR 1.8, log-rank P=.03
OS: No significant difference between arms
Sidedness: Left-sided primaries comparable across arms; right-sided trended toward better outcomes with bevacizumab
mPFS: 8.3 mo (cetuximab) vs 5.9 mo (bevacizumab); HR 1.8, log-rank P=.03
OS: No significant difference between arms
Sidedness: Left-sided primaries comparable across arms; right-sided trended toward better outcomes with bevacizumab
Adverse events
Overall: No new or unexpected toxicities were observed with either combination
Expected class effects: Anti-EGFR skin toxicity in the cetuximab arm; anti-VEGF effects (e.g., hypertension) in the bevacizumab arm, consistent with prior FOLFOXIRI + targeted-agent experience; detailed grade 3–4 rates NR in primary report
Expected class effects: Anti-EGFR skin toxicity in the cetuximab arm; anti-VEGF effects (e.g., hypertension) in the bevacizumab arm, consistent with prior FOLFOXIRI + targeted-agent experience; detailed grade 3–4 rates NR in primary report
Conclusions
FOLFOXIRI + cetuximab did not achieve a higher ORR than FOLFOXIRI + bevacizumab in BRAF V600E-mutant mCRC; bevacizumab-based chemotherapy remains the preferred initial backbone in this population.
Key Limitations
Small phase 2 trial (n=107) with 2:1 randomization limiting precision in the smaller bevacizumab arm. Detailed safety and final OS data were not fully reported in the primary analysis. BRAF V600E mutation predicts poor anti-EGFR responsiveness, so cetuximab was biologically disadvantaged from the outset.
Clinical Context
FIRE-4.5 confirmed that anti-EGFR antibodies offer no advantage over bevacizumab when added to first-line FOLFOXIRI in BRAF V600E-mutant mCRC. ESMO recommends a chemotherapy doublet/triplet + bevacizumab first-line for BRAF V600E disease, with encorafenib + cetuximab reserved for the second-line setting per BEACON CRC.