FDA Grants Full Approval to Braftovi Combination for First-Line BRAF V600E–Mutant Metastatic Colorectal Cancer

The FDA has granted full approval to the combination of Braftovi (encorafenib; Pfizer) plus Erbitux (cetuximab) and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation. The regulatory action, which converts the regimen’s December 2024 accelerated approval into full approval, was based on progression-free survival (PFS) and overall survival (OS) data from the Phase III BREAKWATER trial (NCT04607421).^1,2

“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,” Aamir Malik, executive vice president and chief U.S. Commercial Officer, Pfizer, said in a press release. “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.”¹

Regulatory Decision Converts Accelerated to Full Approval in BRAF V600E–Mutant mCRC

Braftovi plus cetuximab and mFOLFOX6 previously received accelerated approval in December 2024 based on objective response rate (ORR) results from BREAKWATER, the results of which were presented at the 2025 American Society of Clinical Oncology Annual Meeting and published in The New England Journal of Medicine (NEJM).³

The full approval is supported by statistically significant improvements in PFS and OS from the Phase III portion evaluating Braftovi in combination with cetuximab and mFOLFOX6, as well as additional ORR data from a separate cohort assessing Braftovi plus cetuximab and FOLFIRI.

Scott Kopetz, MD, PhD, 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, added that the data provide oncologists with the evidence needed to adopt the regimen as a first-line standard of care in this biomarker-defined population.

Braftovi Mechanism of Action as a BRAF Kinase Inhibitor

• Braftovi is an oral small molecule kinase inhibitor that selectively targets BRAF V600E.
• The agent inhibits aberrant activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK), which is implicated in tumor cell proliferation and survival in several cancers, including colorectal cancer.
• BRAF V600E mutations occur in approximately 8% to 12% of patients with mCRC and are associated with poor prognosis and increased mortality risk compared with patients without the mutation.

“Encorafenib is a highly selective, ATP-competitive, small-molecule BRAF inhibitor with antiproliferative and apoptotic activity in tumor cells expressing BRAF V600E mutations and has longer pharmacodynamic activity than other approved BRAF inhibitors,” the authors wrote in NEJM. “In colorectal cancer, BRAF inhibition alone can cause the BRAF pathway to be reactivated by epidermal growth factor receptor (EGFR) owing to feedback loops within the signaling network (also known as rapid pathway feedback reactivation), which attenuates the activity of BRAF inhibitors. The value of targeting BRAF simultaneously with EGFR inhibition to overcome reactivation has been shown previously.”3

BREAKWATER Trial Design and Patient Population

• BREAKWATER is a global, randomized, active-controlled, open-label, multicenter Phase III trial evaluating Braftovi with cetuximab, alone or in combination with mFOLFOX6 or FOLFIRI, in patients with previously untreated BRAF V600E–mutant mCRC.
• In the Phase III portion, patients were randomly assigned to receive Braftovi 300 mg orally once daily plus cetuximab and mFOLFOX6 (n=236) or chemotherapy (mFOLFOX6, FOLFOXIRI, or CAPOX) with or without bevacizumab (n=243).
• Dual primary endpoints were ORR and PFS as assessed by blinded independent central review (BICR); OS was a key secondary endpoint.
• In Cohort 3, patients were randomly assigned to Braftovi plus cetuximab and FOLFIRI (n=73) or FOLFIRI with or without bevacizumab (n=74).
• The primary endpoint was ORR by BICR, with PFS and OS as secondary endpoints.

Progression-Free Survival and Overall Survival Outcomes

• At the time of primary PFS analysis, Braftovi plus cetuximab and mFOLFOX6 reduced the risk of disease progression or death by 47% compared with chemotherapy with or without bevacizumab (HR 0.53; 95% CI, 0.41–0.68; p<0.0001).
• Median PFS was 12.8 months with the Braftovi combination regimen compared with 7.1 months in the control arm.
• In a second interim OS analysis, the Braftovi combination reduced the risk of death by 51% compared with chemotherapy with or without bevacizumab (HR 0.49; 95% CI, 0.38–0.63; p<0.0001).
• Median OS improved from 15.1 months in the control arm to 30.3 months with BRAFTOVI plus cetuximab and mFOLFOX6.

Objective Response Results in FOLFIRI Cohort

• In Cohort 3, Braftovi plus cetuximab and FOLFIRI demonstrated a statistically significant improvement in confirmed ORR compared with FOLFIRI with or without bevacizumab (64% vs 39%; odds ratio 2.76; p=0.0011).
• Detailed PFS data from this cohort are expected to be presented at an upcoming medical meeting.

Braftovi Safety Profile

• The safety profile of both combination regimens was consistent with the known safety profiles of the individual agents, with no new safety signals identified.
• The most common adverse events (AEs) (≥25%) with the mFOLFOX6 regimen included peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation.
• The most common AEs (≥25%) with the FOLFIRI regimen included nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.
• Permanent discontinuation of Braftovi due to AEs occurred in 14% of patients receiving the mFOLFOX6 regimen and 9% of those receiving the FOLFIRI regimen.

Colorectal cancer remains the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related death. Approximately 20% of patients present with metastatic disease at diagnosis, and up to half of those with localized disease eventually develop metastases.

The approval of Braftovi-based combination therapy provides a biomarker-driven, first-line treatment option for patients with previously untreated BRAF V600E–mutant metastatic colorectal cancer.

References

1. U.S. FDA Grants Full Approval to Pfizer’s BRAFTOVI Combination Regimen in First-Line Metastatic Colorectal Cancer. News release. Pfizer. February 24, 2026. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-grants-full-approval-pfizers-braftovi-combination

2. A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer. ClinicalTrials.gov. Updated August 14, 2025. Accessed February 25, 2026. https://clinicaltrials.gov/study/NCT04607421

3. Elez E., et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med 2025; DOI: 10.1056/NEJMoa2501912.