Pfizer announced detailed progression-free and overall survival results from Cohort 3, a randomized cohort of the Phase 3 BREAKWATER trial, evaluating BRAFTOVI® (encorafenib) in combination with cetuximab (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 presented 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 progression-free survival (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% 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% Confidence Interval [CI], 0.27–0.70; p=0.0002).
Updated overall survival (OS), a descriptive secondary endpoint, showed a 44% reduction in the risk of death for patients treated with the BRAFTOVI combination regimen versus the comparator (HR of 0.56; 95% CI, 0.34–0.94) with a median follow-up of approximately 20 months for both arms. At 18 months, 72% of patients receiving the BRAFTOVI combination regimen were expected to be alive compared to 54.5% 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.
“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,” said Scott Kopetz, M.D., Ph.D., 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. “A nearly 60% 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.”
“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,” said Jeff Legos, Chief Oncology Officer, Pfizer. “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.”
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%) 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% of patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI compared to 80.9% of patients receiving FOLFIRI with or without bevacizumab. Treatment discontinuation occurred in 15.5% of patients receiving the BRAFTOVI combination compared to 10.3% for those receiving FOLFIRI.
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 U.S. Food and Drug Administration (FDA) for patients with BRAF V600E-mutant mCRC in February 2026, offering flexibility in chemotherapy regimen used.
Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries.
About BREAKWATER
BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with chemotherapy (mFOLFOX6 or FOLFIRI) in participants with previously untreated BRAF V600E-mutant mCRC. Patients were randomized to receive BRAFTOVI 300 mg orally once daily in combination with cetuximab (discontinued after randomization of 158 patients), BRAFTOVI 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n=236) or mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab (control arm) (n=243). The dual primary endpoints for these study groups are ORR and PFS as assessed by BICR. OS is a key secondary endpoint. In Cohort 3, patients were randomized to receive BRAFTOVI 300 mg orally once daily in combination with cetuximab and FOLFIRI (n=73) or FOLFIRI, with or without bevacizumab (control-arm) (n=74). The primary endpoint of Cohort 3 is ORR as assessed by BICR. PFS as assessed by BICR is a key secondary endpoint; OS is a secondary endpoint.
About Colorectal Cancer (CRC)
CRC is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022.1 It is the second leading cause of cancer-related deaths.2 Overall, the lifetime risk of developing CRC is about 1 in 24 for men and 1 in 26 for women.2 In the U.S. alone, an estimated 158,850 people will be diagnosed with cancer of the colon or rectum in 2026, and approximately 55,000 are estimated to die from the disease each year.3 For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat, and up to 50% of patients with localized disease eventually develop metastases.4
BRAF mutations are estimated to occur in 8-12% of people with mCRC and are associated with a poor prognosis for these patients.5 The BRAF V600Emutation is the most common BRAF mutation, and the risk of mortality in CRC patients with the BRAF V600Emutation is more than double that of patients with no known mutation present.5-7 Despite the high unmet need in BRAF V600E–mutant mCRC, prior to the BRAFTOVI accelerated FDA approval in this indication on December 20, 2024, there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E–mutant mCRC.8,9
About BRAFTOVI® (encorafenib)
BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E. Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in certain cancers, including CRC.
Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize the product in Japan and South Korea, Medison has exclusive rights to commercialize the product in Israel, and Pierre Fabre Laboratories has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea).
References
- American Cancer Society. Global Cancer Facts & Figures 5th Edition. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-2024.pdf. Last accessed: May 2026.
- American Cancer Society. Key Statistics for Colorectal Cancer. Available at: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html. Last accessed: May 2026.
- American Cancer Society. Cancer Facts & Figures 2026. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2026/2026-cancer-facts-and-figures.pdf. Last accessed: May 2026.
- Ciardiello F, Ciardiello D, Martini G, et al. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72:372–40.
- Tabernero J, Ros J, Élez E. The evolving treatment landscape in BRAF-V600E–mutated metastatic colorectal cancer. Am Soc Clin Oncol Educ Book. 2022;42:254-263. doi:10.1200/EDBK_349561
- Ardekani GS, Jafarnejad SM, Tan L, et al. The prognostic value of BRAF mutation in colorectal cancer and melanoma: A systematic review and meta-analysis. PLoS ONE. 2012;7(10):e47054.
- Schirripa M, Biason P, Lonardi S, et al. Class 1, 2, and 3BRAF-mutated metastatic colorectal cancer: A detailed clinical, pathologic, and molecular characterization. Clin Cancer Res. 2019;25(13):3954-3961. doi:10.1158/1078-0432.CCR-19-0311
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Colon Cancer. V.5.2025 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed November 2025. To view the most recent and complete version of the guideline, go online to NCCN.org.
- Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32.