Pfizer reported detailed progression-free and overall survival results from Cohort 3 of the Phase 3 BREAKWATER trial evaluating BRAFTOVI (encorafenib) in combination with cetuximab (ERBITUX) and FOLFIRI versus FOLFIRI with or without bevacizumab in previously untreated metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. The randomized cohort, to be presented in a late-breaking oral session at the 2026 American Society of Clinical Oncology Annual Meeting and published in Annals of Oncology, previously met its primary endpoint of objective response rate by blinded independent central review.
For the key secondary endpoint of progression-free survival, median PFS was 15.2 months with the BRAFTOVI combination regimen compared with 8.3 months for the comparator arm. This corresponded to a 56% reduction in the risk of disease progression or death (hazard ratio 0.44; 95% CI, 0.27–0.70; p=0.0002). Updated overall survival, a descriptive secondary endpoint, showed a 44% reduction in the risk of death for patients receiving the BRAFTOVI combination versus the comparator (hazard ratio 0.56; 95% CI, 0.34–0.94) with a median follow-up of about 20 months in both arms. At 18 months, 72% of patients in the BRAFTOVI arm were expected to be alive versus 54.5% in the comparator arm, and median overall survival was not reached with the BRAFTOVI combination compared with 20.3 months for the comparator.
Scott Kopetz, MD, PhD, FACP, of The University of Texas MD Anderson Cancer Center and co‑principal investigator of BREAKWATER, said the data support the role of encorafenib plus cetuximab and FOLFIRI as a standard of care in the first-line setting for patients with BRAF V600E-mutant mCRC. Jeff Legos, chief oncology officer at Pfizer, said the findings add to evidence supporting the BRAFTOVI combination as a cornerstone of first-line treatment across two chemotherapy backbones in this population.
In Cohort 3, the safety profile of BRAFTOVI with cetuximab and FOLFIRI remained consistent with the known profiles of the individual agents, and no new safety signals were observed. The most common adverse events (occurring in at least 25% of patients) with the BRAFTOVI regimen were nausea, diarrhea, vomiting, anemia, alopecia, fatigue, decreased neutrophil count, constipation, decreased appetite, neutropenia, arthralgia, asthenia, and abdominal pain. Grade 3 or higher adverse events (all causality) occurred in 70.4% of patients receiving the BRAFTOVI combination versus 80.9% of those receiving FOLFIRI with or without bevacizumab. Treatment discontinuation rates were 15.5% with the BRAFTOVI regimen and 10.3% with the comparator.
Based on the overall Phase 3 data and Cohort 3 results from BREAKWATER, BRAFTOVI in combination with cetuximab and fluorouracil-based chemotherapy received full U.S. Food and Drug Administration approval with an expanded indication for patients with BRAF V600E-mutant mCRC in February 2026, allowing flexibility in the choice of chemotherapy backbone. Pfizer is also providing plain language summaries of company-sponsored research presented at medical meetings, which are intended to help non‑scientists understand the findings.
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