EC (encorafenib+BRAF inhibitor) + cetuximab (EGFR mAb) + FOLFIRI cuts PFS risk ~56% in 1L BRAF V600E mCRC

Encorafenib (BRAF inhibitor) plus cetuximab (EGFR antibody) was combined with FOLFIRI chemotherapy as first-line treatment in BREAKWATER Cohort 3 (Phase 3, open-label; NCT04607421) for untreated BRAF V600E–mutant metastatic colorectal cancer with ECOG 0–1 (n=147; EC+FOLFIRI n=73 vs control FOLFIRI±bevacizumab n=74; data cutoff Jan 6, 2026). EC+FOLFIRI improved median PFS to 15.2 months vs 8.3 months (HR 0.44, one-sided p=0.0002) and showed an OS signal (median OS not estimable vs 20.3 months; HR 0.56; 18-mo OS 72.0% vs 54.5%). Chemo discontinuation due to AEs was similar (14% vs 10%), with serious TEAEs 49% vs 44% and max grade 3/4 TEAEs 70% vs 81%—notably, efficacy appears well beyond typical FOLFIRI±bevacizumab benchmarks in this biomarker-defined high-risk subtype (BRAF V600E in ~7–10% of mCRC), while tolerability looks broadly comparable to control.