Pfizer has announced detailed Progression-Free and Overall Survival results from Cohort 3, a randomised cohort of the phase 3 BREAKWATER trial, evaluating BRAFTOVI (encorafenib) in combination with cetuximab (marketed as ERBITUX) and FOLFIRI (fluorouracil, leucovorin, and irinotecan) versus FOLFIRI with or without bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. These results will be presented today in a late-breaking oral presentation (Abstract LBA3503) at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the Annals of Oncology.

As previously reported, Cohort 3 met its primary endpoint of Objective Response Rate (ORR) by Blinded Independent Central Review (BICR). Results for the key secondary endpoint of PFS by BICR, being presented at ASCO, show median PFS was nearly doubled with the BRAFTOVI combination regimen (15.2 months) versus the comparator (8.3 months). A clinically meaningful and statistically significant 56 percent reduction in the risk of disease progression or death was observed for patients treated with the BRAFTOVI combination regimen versus the comparator (Hazard Ratio [HR] of 0.44; 95 percent Confidence Interval [CI], 0.27–0.70; p=0.0002).

Updated Overall Survival (OS), a descriptive secondary endpoint, showed a 44 percent reduction in the risk of death for patients treated with the BRAFTOVI combination regimen versus the comparator (HR of 0.56; 95 percent CI, 0.34-0.94) with a median follow-up of approximately 20 months for both arms. At 18 months, 72 percent of patients receiving the BRAFTOVI combination regimen were expected to be alive compared to 54.5 percent of patients receiving the comparator. Median OS was not reached for the BRAFTOVI combination regimen versus a median of 20.3 months for the comparator.

Scott Kopetz, MD, PhD, FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas, MD, Anderson Cancer Center and co-principal investigator of the BREAKWATER trial, said, “For people with BRAF V600E-mutant metastatic colorectal cancer–a disease that historically has had no targeted treatment options and poor outcomes–these results strengthen confidence in how we can treat this disease. A nearly 60 percent reduction in risk of disease progression or death, combined with prolonged overall survival, reinforces the role of encorafenib in combination with cetuximab and FOLFIRI as a standard of care in the first-line setting for this patient population.”

In this Cohort 3 analysis, the safety profile of BRAFTOVI in combination with cetuximab and FOLFIRI continued to be consistent with the known safety profile of each respective agent in the regimen, and no new safety signals were identified. The most common adverse events (AEs) (≥25 percent) in the BRAFTOVI regimen were nausea, diarrhea, vomiting, anemia, alopecia, fatigue, decreased neutrophil count, constipation, decreased appetite, neutropenia, arthralgia, asthenia, and abdominal pain. Grade ≥3 AEs (all causality) occurred in 70.4 percent of patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI compared to 80.9 percent of patients receiving FOLFIRI with or without bevacizumab. Treatment discontinuation occurred in 15.5 percent of patients receiving the BRAFTOVI combination compared to 10.3 percent for those receiving FOLFIRI.

Jeff Legos, Chief Oncology Officer, Pfizer, said, "These compelling results add to a robust body of evidence demonstrating the efficacy of the BRAFTOVI combination treatment across 2 different established chemotherapy regimens in BRAF V600E-mutant metastatic colorectal cancer. These findings reaffirm the established role of the BRAFTOVI combination regimen as a cornerstone of first-line treatment for patients and families facing this challenging diagnosis.”

Based on the totality of the Phase 3 and Cohort 3 data in the BREAKWATER study, BRAFTOVI in combination with cetuximab and fluorouracil-based chemotherapy received full approval with an expanded indication from the US Food and Drug Administration (FDA) for patients with BRAF V600E-mutant mCRC in February 2026, offering flexibility in chemotherapy regimen used.