On February 24, the U.S. Food and Drug Administration (FDA) granted traditional approval to the kinase inhibitor encorafenib (Braftovi) in combination with cetuximab and fluorouracil-based chemotherapy for the treatment of adult patients with metastatic colorectal cancer 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 a BRAF V600E mutation in 2024.
BREAKWATER
Efficacy was evaluated in the BREAKWATER trial (ClinicalTrials.gov identifier NCT04607421), a randomized, active-controlled, open-label, multicenter trial in patients with treatment-naive, BRAF V600E mutation–positive, metastatic colorectal cancer, as detected using the Qiagen therascreen BRAF V600E RGQ PCR Kit.
The phase III portion of BREAKWATER initially randomly assigned patients 1:1:1 to one of the following three arms:
- Encorafenib orally once daily with cetuximab intravenous (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)
- 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, with patients randomly assigned 1:1:
- Encorafenib orally once daily with cetuximab IV infusion every 2 weeks and FOLFIRI every 2 weeks (experimental, Arm D)
- 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 III Portion of BREAKWATER
The major efficacy outcome measures were progression-free survival in all randomly assigned patients and objective response rate in the first 110 patients randomly assigned in each arm per blinded independent, central review. Overall survival in all patients was an additional formally tested outcome measure. A total of 236 patients were randomly assigned to the investigational Arm B and 243 to the control, Arm C.
Median progression-free survival was 12.8 months (95% confidence interval [CI] = 11.2–15.9 months) in Arm B and 7.1 months (95% CI = 6.8–8.5 months) in Arm C (hazard ratio [HR] = 0.53, 95% CI = 0.41–0.68, P < .0001). Median overall survival was 30.3 months (95% CI = 21.7 months to not estimable) and 15.1 months (95% CI = 13.7–17.7 months) (HR = 0.49, 95% CI = 0.38–0.63), P < .0001). Objective response rate was 61% (95% CI = 52%–70%) and 40% (95% CI = 31%–49%) (P = .0008) in the respective arms.
Cohort 3 Portion of BREAKWATER
The major efficacy outcome measure was objective response rate per blinded independent central review; 73 patients were randomly assigned to investigational Arm D and 74 to the control, Arm E. The objective response rate was 64% (95% CI = 53%–74%) in Arm D, compared to 39% (95% CI = 29%–51%) in Arm E (P = .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 which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Health Canada. The application reviews are ongoing at the other regulatory agencies.
This review used the Real-Time Oncology Review 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.
