Background
Phase 3 RCT (BREAKWATER, Cohort 3); N=147; previously untreated BRAF V600E–mutant metastatic colorectal cancer (mCRC). Tests encorafenib + cetuximab (EC) added to FOLFIRI versus a FOLFIRI ± bevacizumab control.
Results
Interventions and follow up: Arm A: Encorafenib 300 mg daily + cetuximab 500 mg/m² q2w + FOLFIRI (n=73)
Arm B: FOLFIRI ± bevacizumab (control) (n=74)
Primary endpoint: ORR by BICR
Key secondary endpoint: PFS by BICR
mFollow up: NR
Results: ORR (BICR): 64.4% vs 39.2%; OR 2.76, 95% CI 1.42–5.35; P=.0011
PFS (BICR): 15.2 vs 8.3 mo; HR 0.44, 95% CI 0.27–0.70; P=.0002
OS: NR vs 20.3 mo; HR 0.56, 95% CI 0.34–0.94
Arm B: FOLFIRI ± bevacizumab (control) (n=74)
Primary endpoint: ORR by BICR
Key secondary endpoint: PFS by BICR
mFollow up: NR
Results: ORR (BICR): 64.4% vs 39.2%; OR 2.76, 95% CI 1.42–5.35; P=.0011
PFS (BICR): 15.2 vs 8.3 mo; HR 0.44, 95% CI 0.27–0.70; P=.0002
OS: NR vs 20.3 mo; HR 0.56, 95% CI 0.34–0.94
Adverse events
Serious AEs: 49.3% vs 44.1%
Profile: consistent with the known profile of each agent; no new safety signals
Profile: consistent with the known profile of each agent; no new safety signals
Conclusions
In first-line BRAF V600E–mutant mCRC, encorafenib + cetuximab + FOLFIRI significantly improved ORR and PFS with prolonged OS versus chemotherapy ± bevacizumab, supporting EC + fluorouracil-based chemotherapy as an additional first-line standard of care and providing a validated irinotecan-based backbone.
Key Limitations
Modest sample size (N=147) in one cohort of a larger program; OS not yet mature (median NR in the experimental arm). Control allowed but did not mandate bevacizumab; cross-comparison with the mFOLFOX6 cohort is informal. Open-label regimen.
Clinical Context
Complements the BREAKWATER mFOLFOX6 cohort (OS 30.3 vs 15.1 mo, HR 0.49). On Feb 24, 2026 the FDA granted traditional approval to encorafenib + cetuximab + fluorouracil-based chemotherapy (FOLFIRI or FOLFOX) for first-line BRAF V600E mCRC (accelerated approval Dec 2024 with mFOLFOX6). NCCN and ESMO recommend encorafenib + cetuximab–based regimens for BRAF V600E mCRC; this validates an irinotecan-based alternative.