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The BRAFTOVI combination regimen is the only approved targeted regimen for first-line BRAF-V600E mutant metastatic colorectal cancer
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Pivotal results from the Phase 3 portion with mFOLFOX6 of the BREAKWATER trial demonstrated a clinically meaningful and statistically significant 51% risk reduction in death and a 47% risk reduction in disease progression or death compared to chemotherapy treatment with or without bevacizumab
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Expanded indication enables flexibility to use BRAFTOVI in combination with cetuximab and different fluorouracil-based chemotherapy regimens
February 24--NEW YORK--(BUSINESS WIRE)-- Pfizer Inc. (NYSE: PFE) today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation based on results from the global Phase 3 BREAKWATER trial (NCT04607421).
BRAFTOVI in combination with cetuximab and mFOLFOX6 was granted accelerated approval by the FDA in December 2024 based on objective response rate (ORR) results, one of the BREAKWATER trial’s dual primary endpoints. The conversion from accelerated approval to full approval is based on significant benefit in outcomes for both progression-free survival (PFS), the trial’s other primary endpoint, and overall survival (OS), a key secondary endpoint, from the Phase 3 portion of the study that evaluated BRAFTOVIin combination with cetuximab and mFOLFOX6, as well as the ORR results from the Cohort 3 portion of the study, which evaluated BRAFTOVIin combination with cetuximab and FOLFIRI.
“This landmark approval, achieved through the robust clinical benefit demonstrated in the BREAKWATER trial, validates that this targeted therapy can impact outcomes for people living with an aggressive, hard-to-treat cancer,” said Aamir Malik, Executive Vice President, Chief U.S. Commercial Officer, Pfizer. “As the only targeted combination regimen shown to deliver a significant improvement in certain outcomes for patients with BRAF V600E‑mutant metastatic colorectal cancer, BRAFTOVI is uniquely positioned to redefine first‑line treatment and establish a new standard of care. This approval reinforces our leadership in bringing differentiated, potentially practice‑changing cancer therapies to patients and healthcare providers who urgently need improved options.”
“This approval gives oncologists confidence to use encorafenib plus cetuximab in combination with fluorouracil-based chemotherapy as a first-line standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer,” 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. “The BREAKWATER study demonstrated that these targeted combination regimens provided statistically significant benefit, providing the robust evidence we need to make treatment decisions that can meaningfully impact patient outcomes.”
In the BREAKWATER study, the safety profile of both combination regimens continued to be consistent with the known safety profile of each respective agent in the regimen. No new safety signals were identified. The most common side effects (≥25%) in the mFOLFOX6 regimen were peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation. The most common side effects (≥25%) in the FOLFIRI regimen were nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.
Among patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6, 14% experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI. There was no substantial difference in chemotherapy discontinuation due to side effects in the BRAFTOVI in combination with cetuximab and mFOLFOX6 arm compared with the chemotherapy, with or without bevacizumab arm. Among patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, 9% experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI.
The BRAFTOVI combination regimen with mFOLFOX6 is also under regulatory review in Europe, where Pierre Fabre Laboratories has exclusive commercialization rights, and was recently approved for use in several other countries.
About BREAKWATER
BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with mFOLFOX6 or FOLFIRI (both fluorouracil-based chemotherapies) in participants with previously untreated BRAF V600E-mutant mCRC.
Phase 3 Analysis: BRAFTOVI in combination with cetuximab and mFOLFOX6:
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.
At the time of the PFS primary analysis, BRAFTOVI in combination with cetuximab and mFOLFOX6 significantly reduced the risk of disease progression or death by 47% compared to chemotherapy with or without bevacizumab (hazard ratio [HR] 0.53; 95% confidence interval [CI], 0.41, 0.68; p<0.0001) as assessed by blinded independent central review (BICR). Median PFS was 12.8 months (95% CI, 11.2, 15.9) with the BRAFTOVI combination regimen compared to 7.1 months (95% CI, 6.8, 8.5) with chemotherapy with or without bevacizumab. In a second interim analysis of median OS, BRAFTOVI plus cetuximab and mFOLFOX6 significantly reduced the risk of death by 51% compared to chemotherapy, with or without bevacizumab (HR 0.49; 95% CI, 0.38, 0.63; p<0.0001). Median OS doubled from 15.1 months with chemotherapy, with or without bevacizumab (95% CI, 13.7, 17.7) to 30.3 months (95% CI, 21.7, Not Estimated) with the BRAFTOVI combination regimen. These data were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine.
Cohort 3 Analysis: BRAFTOVI in combination with cetuximab and FOLFIRI:
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 is a key secondary endpoint; OS is a secondary endpoint summarized descriptively.
BRAFTOVI plus cetuximab and FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR assessed by BICR compared to patients receiving FOLFIRI with or without bevacizumab (64% vs 39%, odds ratio =2.76, p=0.0011). These data were presented at the 2026 American Society of Clinical Oncology Gastrointestinal (ASCO GI®) Cancers Symposium. Detailed PFS results from Cohort 3 will be submitted for presentation at an upcoming medical meeting.
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 V600E mutation is the most common BRAF mutation, and the risk of mortality in CRC patients with the BRAF V600E mutation 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).
About Pfizer Oncology
At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and multispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, gastrointestinal cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives.
About Pfizer: Breakthroughs That Change Patients’ Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us.
References
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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: February 2026.
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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: February 2026.
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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.
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Josep Tabernero et al. 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
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Safaee Ardekani G, 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.
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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
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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.
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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.