On December 20, 2024, the Food and Drug Administration granted accelerated approval to encorafenib (Braftovi, Array BioPharma Inc., a subsidiary of Pfizer Inc.) with cetuximab and mFOLFOX6 for patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test.

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

Efficacy and Safety

Efficacy was evaluated in BREAKWATER (NCT04607421), an active-controlled, open-label, multicenter trial. Patients were required to have treatment naïve BRAF V600E mutation-positive mCRC, detected by the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit. Patients were initially randomized 1:1:1 to one of the following treatment arms:

• encorafenib orally once daily with cetuximab IV infusion every 2 weeks (encorafenib+cetuximab arm),
• encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (encorafenib+cetuximab+mFOLFOX6 arm), or
• mFOLFOX6, FOLFOXIRI (both every 2 weeks) or CAPOX (every 3 weeks)-each with or without bevacizumab (control arm).

The trial was subsequently amended to limit randomization (1:1) to the encorafenib +cetuximab+mFOLFOX6 arm and the control arm. Treatment in all arms continued until disease progression, unacceptable toxicity, consent withdrawal, lost to follow-up, or death. The results of the encorafenib + cetuximab + mFOLFOX6 arm compared to the control arm served as the basis of this accelerated approval and are described below.

The major efficacy outcome measure was confirmed objective response rate (ORR) assessed by blinded independent central review and evaluated in the first 110 patients randomized in each arm. ORR was 61% (95% CI: 52%, 70%) in the encorafenib+ cetuximab, + mFOLFOX6 arm and 40% (95% CI: 31%, 49%) in the control arm. Median DoR was 13.9 months (95% CI: 8.5, not estimable) and 11.1 months (95% CI: 6.7, 12.7) in the respective arms.

Evaluation of progression-free survival and overall survival in the ongoing BREAKWATER trial will serve as post-marketing confirmatory evidence for this accelerated approval. This application is an example of the Oncology Center of Excellence's Project FrontRunner aimed at moving important therapies to earlier disease settings.

The most common adverse reactions (≥25%) were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia. The most common Grade 3 or 4 laboratory abnormalities (≥20%) were increased lipase and decreased neutrophil count.

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

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 review is ongoing at the other regulatory agencies.