On February 24, 2026, Pfizer Inc. announced that the U.S. Food and Drug Administration (FDA) has formally approved Braftovi® (encorafenib) in combination with cetuximab (Erbitux) and a fluoropyrimidine-based chemotherapy regimen for the treatment of adult patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC).

The approval is based on results from the global Phase III BREAKWATER trial (NCT04607421).

The Braftovi combination regimen is the only approved targeted therapy for the first-line treatment of BRAF V600E-mutant metastatic colorectal cancer.

About the BREAKWATER Trial

BREAKWATER is a Phase III, randomized, active-controlled, open-label, multicenter trial enrolling previously untreated patients with BRAF V600E-mutant metastatic colorectal cancer. It evaluated the efficacy and safety of Braftovi plus cetuximab, administered alone or in combination with mFOLFOX6 or FOLFIRI (both fluoropyrimidine-based chemotherapy regimens).

Phase III Analysis: Braftovi + Cetuximab + mFOLFOX6

Patients were randomized into three groups:

Braftovi 300 mg orally once daily plus cetuximab (cetuximab was discontinued after 158 patients were randomized);

Braftovi 300 mg orally once daily plus cetuximab and mFOLFOX6 (n=236);

mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab (control arm, n=243).

The dual primary endpoints of the study were Objective Response Rate (ORR) and Progression-Free Survival (PFS) assessed by Blinded Independent Central Review (BICR). Overall Survival (OS) was a key secondary endpoint.

Cohort 3 Analysis: Braftovi + Cetuximab + FOLFIRI

In Cohort 3, patients were randomized into two groups:

Braftovi 300 mg orally once daily plus cetuximab and FOLFIRI (n=73);

FOLFIRI with or without bevacizumab (control arm, n=74).

The primary endpoint of Cohort 3 was ORR assessed by BICR. PFS was a key secondary endpoint, and OS was a descriptive secondary endpoint.

About Colorectal Cancer

Colorectal cancer is the third most common cancer worldwide, with approximately 1.8 million new cases globally in 2022, and the second leading cause of cancer-related death.

Overall, the lifetime risk of developing colorectal cancer is about 1 in 24 for men and 1 in 26 for women.

In the United States alone, approximately 158,850 people are expected to be diagnosed with colorectal cancer in 2026, with about 55,000 deaths from the disease each year.

Distant metastasis is present at diagnosis in 20% of patients with colorectal cancer, significantly increasing treatment difficulty; approximately 50% of patients with localized disease will eventually develop metastasis.

BRAF mutations occur in approximately 8%–12% of patients with metastatic colorectal cancer and are associated with poor prognosis.

BRAF V600E is the most prevalent subtype, and patients with this mutation have more than twice the risk of death compared with patients without known mutations.

Despite the substantial unmet medical need for BRAF V600E-mutant metastatic colorectal cancer, no biomarker-driven therapy for previously untreated patients with this disease had been approved globally prior to the FDA’s accelerated approval of Braftovi for this indication on December 20, 2024.

About Braftovi (encorafenib)

Braftovi is an oral small-molecule kinase inhibitor that selectively targets BRAF V600E.

Dysregulation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been proven to contribute to the development and progression of many cancers, including colorectal cancer.

Indications and Usage

Braftovi (encorafenib) is indicated, in combination with cetuximab and fluoropyrimidine-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation detected by an FDA-approved test.

Limitations of Use

Braftovi is not indicated for the treatment of patients with colorectal cancer that is BRAF wild-type.