On December 20, 2024, the U.S. Food and Drug Administration granted accelerated approval to encorafenib (Braftovi) in combination with cetuximab and modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) for patients with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test.
Multicenter Trial
Efficacy was evaluated in BREAKWATER (ClinicalTrials.gov identifier NCT04607421), an active-controlled, open-label, multicenter trial. Patients were required to have treatment-naive BRAF V600E mutation–positive metastatic colorectal cancer, as detected by the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit.
Patients were initially randomly assigned 1:1:1 to one of the following treatment arms: encorafenib orally once daily with cetuximab IV infusion every 2 weeks (encorafenib plus cetuximab arm); encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (encorafenib plus cetuximab plus mFOLFOX6 arm); or mFOLFOX6 or FOLFOXIRI (leucovorin, fluorouracil, oxaliplatin, and irinotecan), both every 2 weeks), or capecitabine plus oxaliplatin (every 3 weeks), each with or without bevacizumab (control arm).
The trial was subsequently amended to limit randomization (1:1) to the encorafenib plus cetuximab plus 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 plus cetuximab plus mFOLFOX6 arm compared to the control arm served as the basis of this accelerated approval.
Key Findings
The major efficacy outcome measure was confirmed objective response rate assessed by blinded independent central review and evaluated in the first 110 patients randomly assigned in each arm. Objective response rate was 61% (95% confidence interval [CI] = 52%–70%) in the encorafenib plus cetuximab plus mFOLFOX6 arm and 40% (95% CI = 31%–49%) in the control arm. Median duration of response was 13.9 months (95% CI = 8.5 to 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 postmarketing confirmatory evidence for this accelerated approval.
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 until disease progression or unacceptable toxicity. Full dosing information is provided in the prescribing information.
