Top results from Cohort 3 of the Phase 3 BREAKWATER trial show that combining Braftovi (encorafenib), Erbitux (cetuximab), and FOLFIRI significantly improves outcomes for patients with previously untreated BRAF V600E–mutant metastatic colorectal cancer. The study compared this targeted triplet with standard FOLFIRI chemotherapy with or without bevacizumab.
The confirmed overall response rate was 64.4% with the triplet therapy, compared with 39.2% in the standard treatment group. In the experimental arm, 4.1% of patients achieved a complete response and 60.3% had a partial response. Progression-free survival was significantly improved, and overall survival was meaningfully longer compared with standard therapy. The combination also showed a much higher likelihood of response, with an odds ratio of 2.756.
No new safety concerns were identified. Serious side effects were consistent with the known profiles of the individual drugs. Grade 3 or 4 adverse events occurred in 63.4% of patients in the triplet group and 70.6% in the control group. Serious treatment-related events were reported in 23.9% versus 19.1%, respectively. There was no significant increase in fatal events. Earlier data from this trial already led to FDA approval in December 2024 of encorafenib plus cetuximab with mFOLFOX6. These new results suggest that the FOLFIRI-based triplet could also become an important first-line option, offering more flexibility for treating this aggressive BRAF V600E–mutant colorectal cancer subtype.