On February 24, 2026, the Food and Drug Administration granted traditional approval to encorafenib (Braftovi, Array BioPharma Inc., a subsidiary of Pfizer Inc.) in combination with cetuximab and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-authorized test. Encorafenib received accelerated approval in combination with cetuximab and mFOLFOX6 for metastatic colorectal cancer with BRAF V600E mutation in 2024.

Full prescribing information for Braftovi will be posted on Drugs@FDA.

Efficacy and Safety

Efficacy was evaluated in the BREAKWATER trial (NCT04607421), a randomized, active-controlled, open-label, multicenter trial in patients with treatment-naïve, BRAF V600E mutation–positive, metastatic CRC, as detected using the Qiagen “therascreen BRAF V600E RGQ PCR Kit.” The Phase 3 portion of BREAKWATER initially randomized 1:1:1 to one of the following three arms:

  • encorafenib orally once daily with cetuximab IV infusion every 2 weeks (experimental, Arm A),
  • encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (experimental, Arm B), or
  • mFOLFOX6 or FOLFOXIRI (both every 2 weeks) or CAPOX (every 3 weeks), each with or without bevacizumab (control, Arm C).

The trial was subsequently amended to limit randomization (1:1) to Arm B and Arm C, and a new cohort was initiated, Cohort 3, with the following two treatment arms, randomized 1:1:

  • encorafenib orally once daily with cetuximab IV infusion every 2 weeks and FOLFIRI every 2 weeks (experimental, Arm D), or
  • FOLFIRI every 2 weeks, with or without bevacizumab (control, Arm E).

Treatment in all arms continued until disease progression, unacceptable toxicity, consent withdrawal, loss to follow-up, or death.

Phase 3 Portion of BREAKWATER
The major efficacy outcome measures were progression-free survival (PFS) in all randomized patients and objective response rate (ORR) in the first 110 patients randomized in each arm per blinded, independent, central review (BICR). Overall survival in all patients was an additional formally tested outcome measure. A total of 236 patients were randomized to the investigational Arm B and 243 to the control, Arm C.

Median PFS was 12.8 months (95% CI: 11.2, 15.9) in Arm B and 7.1 months (95% CI: 6.8, 8.5) in Arm C (hazard ratio [HR] 0.53 [95% CI: 0.41, 0.68]; p-value <0.0001). Median OS was 30.3 months (95% CI: 21.7, NE) and 15.1 months (95% CI: 13.7, 17.7) (HR 0.49 [95% CI: 0.38, 0.63), respectively; p-value <0.0001). ORR was 61% (95% CI: 52%, 70%) and 40% (95% CI: 31%, 49%) (p-value = 0.0008) in the respective arms.

Cohort 3 Portion of BREAKWATER
The major efficacy outcome measure was ORR per BICR; 73 patients were randomized to investigational Arm D and 74 to the control, Arm E. The ORR was 64% (95% CI: 53, 74) in Arm D, compared to 39% (95% CI: 29, 51) in Arm E (p-value = 0.0011).

Warnings and Precautions

The prescribing information includes warnings and precautions for new primary malignancies (cutaneous and noncutaneous), tumor promotion in BRAF–wild-type tumors, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, QT prolongation, and embryo-fetal toxicity.

The recommended encorafenib dose is 300 mg (four 75 mg capsules) orally once daily in combination with cetuximab and mFOLFOX6 or in combination with cetuximab and FOLFIRI until disease progression or unacceptable toxicity. Full dosing information is provided in the prescribing information.

Project Frontrunner and Project Orbis

This application is an example of the Oncology Center of Excellence’s Project FrontRunner aimed at providing earlier access to therapies in earlier disease settings.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Health Canada. The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.govOncProjectFacilitate@fda.hhs.gov.

Follow the Oncology Center of Excellence on X: @FDAOncology.