Pfizer’s BREAKWATER Trial Shows 51% OS Benefit For BRAFTOVI Combo In BRAF V600E Metastatic Colorectal Cancer

Pfizer has announced statistically significant and clinically meaningful results from the Phase 3 BREAKWATER trial evaluating BRAFTOVI® (encorafenib) in combination with cetuximab and mFOLFOX6 for patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation. The combination therapy showed a 51% reduction in the risk of death versus standard-of-care chemotherapy, with or without bevacizumab, and more than doubled median overall survival (OS) to 30.3 months vs. 15.1 months, respectively. These findings were presented at ASCO 2025 and published in the New England Journal of Medicine.

“Patients with metastatic colorectal cancer whose tumors harbor a BRAF V600E mutation generally face a daunting prognosis, as this aggressive tumor often does not respond well to standard-of-care chemotherapy. The BREAKWATER results are the first promising survival outcomes ever reported for BRAF-mutant metastatic colorectal cancer in the first-line setting, representing a practice-changing breakthrough for patients,” said Elena Élez, M.D., Ph.D., senior investigator at Vall d’Hebron Institute of Oncology in Barcelona, Spain, and co-principal investigator of the BREAKWATER trial. 

The combination also significantly improved progression-free survival (PFS), reducing the risk of disease progression or death by 47%, and extended median PFS to 12.8 months vs. 7.1 months for the control arm. The objective response rate (ORR) by blinded review reached 65.7% with the BRAFTOVI regimen, compared to 37.4% in the chemotherapy group. These updated data reinforce earlier results first presented at ASCO GI 2025 and published in Nature Medicine.

“The BRAFTOVI combination helped significantly reduce the risk of disease progression or death, potentially altering the course of disease for people with metastatic colorectal cancer with a BRAF V600E mutation. These unprecedented results from the BREAKWATER trial further establish the benefit of the BRAFTOVI combination regimen and its potential to become a new standard-of-care, building on Pfizer’s legacy in precision medicine and commitment to delivering breakthrough medicines that help people with cancer live better and longer lives,” said Johanna Bendell, M.D., Chief Oncology Development Officer, Pfizer. 

The safety profile of the combination regimen remained consistent with known profiles of the individual drugs, and no new safety signals were observed. Common side effects included nausea, anemia, diarrhea, and rash, among others. 13.8% of patients experienced adverse events leading to discontinuation of BRAFTOVI. 

“The risk of death for patients with BRAF V600E-mutant metastatic colorectal cancer is more than double compared to those with no known mutation. These survival outcomes from the BREAKWATER study bring renewed hope to patients and their loved ones, providing the possibility of more time together. We are thrilled to see important cancer research propel us closer to our goal of ending this disease,” said Michael Sapienza, Chief Executive Officer, Colorectal Cancer Alliance. 

The therapy received accelerated FDA approval in December 2024 based on ORR, and these survival results are currently being discussed with the FDA to support conversion to full approval in 2025 under Project FrontRunner.