Pfizer’s BRAFTOVI Combo Shows Longer Progression-Free Survival in First-Line BRAF V600E Metastatic Colorectal Cancer

Pfizer on Sunday reported detailed Phase 3 data showing that its first-line BRAFTOVI regimen, combined with cetuximab and the FOLFIRI chemotherapy backbone, significantly extended the time before disease worsening in patients with BRAF V600E-mutant metastatic colorectal cancer, a hard-to-treat subtype of advanced colon and rectal cancer.

Results from Cohort 3 of the BREAKWATER trial, presented in a late-breaking oral session at the American Society of Clinical Oncology annual meeting, showed median progression-free survival of 15.2 months with encorafenib, marketed as BRAFTOVI, plus cetuximab and FOLFIRI. That compared with 8.3 months for patients given control therapy of FOLFIRI with or without bevacizumab. Pfizer said the progression-free survival hazard ratio was 0.44, with a 95% confidence interval of 0.27 to 0.70 and a p-value of 0.0002, representing a 56% reduction in the risk of progression or death.

An updated look at overall survival, which was a descriptive secondary endpoint, also favored the experimental regimen. Pfizer reported an overall survival hazard ratio of 0.56, with a 95% confidence interval of 0.34 to 0.94. Median overall survival was not reached in the encorafenib arm, compared with 20.3 months in the control arm, and estimated 18-month survival was 72% versus 54.5%, respectively. The Cohort 3 analysis included 73 patients in the encorafenib-plus-cetuximab-plus-FOLFIRI group and 74 in the control group, with median follow-up of about 20 months in both arms.

The detailed readout builds on January results in which Pfizer said Cohort 3 met its primary endpoint of objective response rate, or the share of patients whose tumors shrank by a predefined amount. At that time, the company reported an objective response rate of 64.4% for the encorafenib regimen versus 39.2% for standard care, with an odds ratio of 2.76 and a p-value of 0.001. On safety, Pfizer said grade 3 or higher adverse events occurred in 70.4% of patients on the encorafenib regimen and 80.9% on the comparator, while treatment discontinuation rates were 15.5% and 10.3%, respectively.

The new data matter because BRAF V600E mutations are found in roughly 8% to 12% of metastatic colorectal cancers and are associated with poor prognosis. Before BREAKWATER, encorafenib plus cetuximab had already shown activity in previously treated patients in the BEACON trial. BREAKWATER is testing whether that targeted approach can improve outcomes earlier, in the first-line setting. The latest ASCO presentation is especially notable because it provides detailed evidence for the regimen when paired with FOLFIRI, one of the standard chemotherapy backbones used in newly diagnosed metastatic disease, adding to prior evidence with mFOLFOX6.

BREAKWATER is a randomized, active-controlled, open-label, multicenter Phase 3 trial evaluating encorafenib plus cetuximab with or without chemotherapy against standard chemotherapy with or without bevacizumab in previously untreated BRAF V600E-mutant metastatic colorectal cancer. The U.S. Food and Drug Administration granted traditional approval on Feb. 24, 2026, to encorafenib in combination with cetuximab and fluorouracil-based chemotherapy for adults with this disease based on BREAKWATER results, so Sunday’s update adds detail rather than marking a new approval. Pfizer said the findings were published simultaneously in Annals of Oncology. “These compelling results add to a robust body of evidence demonstrating the efficacy of the BRAFTOVI combination treatment across two different established chemotherapy regimens in BRAF V600E-mutant metastatic colorectal cancer,” Jeff Legos, Pfizer’s chief oncology officer, said in a statement.