Breakwater Clinical Trials – BiotechReality – Information Intelligence System for Biopharma

Pfizer Inc. has unveiled historic results from its Phase 3 BREAKWATER trial, announcing that the BRAFTOVI® (encorafenib) combination regimen drastically lowers the risk of death in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). The trial showed a 51% decrease in mortality risk over standard-of-care chemotherapy, a landmark milestone in the treatment of this fast-growing cancer subtype. These findings were published in the journal New England Journal of Medicine. Key Findings of the BREAKWATER Trial Overall Survival (OS): The BRAFTOVI combination therapy of encorafenib, cetuximab (ERBITUX®), and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) provided a median OS of 30.3 months. This compares with 15.1 months seen with usual chemotherapy regimens, with or without bevacizumab.Progression-Free Survival (PFS): The treatment also achieved the trial's co-primary endpoint by lowering the risk of tumor progression or death by 47%, with a median PFS of 12.8 months versus 7.1 months in the control arm.Objective Response Rate (ORR): A reanalysis reaffirmed a 65.7% ORR among patients receiving the BRAFTOVI combination, compared with the 37.4% seen in the standard-of-care arm. 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. Elena Élez, M.D., Ph.D. 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. Johanna Bendell, M.D. The revised objective response rate (ORR) by BICR reaffirmed the progress previously noted with the BRAFTOVI combination regimen over patients on chemotherapy with or without bevacizumab (65.7%; 95% CI, 59.4, 71.4 and 37.4%; 95% CI, 31.6, 43.7, respectively). The median duration of response and median time to response were also sustained from the previous primary analysis. Results of the initial ORR analysis were featured at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and concurrently published in Nature Medicine in January 2025. Further data from an independent arm of the BREAKWATER trial assessing the combination of BRAFTOVI with cetuximab will also be presented at ASCO. About BREAKWATER Participants with previously untreated BRAF V600E-mutant metastatic colorectal cancer (CRC) are being treated in the BREAKWATER phase 3 randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, either alone or in conjunction with mFOLFOX6. BRAFTOVI 300 mg orally once daily in combination with cetuximab (which was discontinued after 158 patients were randomly assigned), BRAFTOVI 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n236), or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (control-arm) (n243) were the alternate treatment options for the patients. ORR and progression-free survival (PFS), as determined by blinded independent central review (BICR), are the two main goals. One important secondary endpoint is overall survival. BRAFTOVI® (encorafenib) BRAF V600E is the target of the oral small-molecule kinase inhibitor BRAFTOVI. It has been demonstrated that several malignancies, particularly colorectal cancer, involve inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Source: PfizerJournal Reference: 1. Kopetz, Scott, et al. "Encorafenib, Cetuximab and Chemotherapy in BRAF-mutant Colorectal Cancer: A Randomized Phase 3 Trial." Nature Medicine, vol. 31, no. 3, 2025, pp. 901-908, DOI: https://doi.org/10.1038/s41591-024-03443-3.2. Elez, Elena et al. “Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.” The New England journal of medicine, 10.1056/NEJMoa2501912. 30 May. 2025, DOI: 10.1056/NEJMoa2501912 Last Modified:

Tag: Breakwater Clinical Trials

Pfizer’s BRAFTOVI® Combination Regimen Halves Mortality Risk in BRAF V600E-Mutant Metastatic Colorectal Cancer

Combination of chemotherapy and dual-targeted treatments Phase III Breakwater Clinical trials supported for BRAF-mutated metastatic colorectal cancer FDA approval

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