FDA Approves Encorafenib/Cetuximab Plus mFOLFOX6 for Advanced BRAF V600E+ CRC

The approval is based on findings from the multicenter BREAKWATER trial.

The FDA has granted accelerated approval to encorafenib (Braftovi) in combination with cetuximab (Erbitux) and mFOLFOX6 for patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test.

The decision was based on findings from the multicenter, active-controlled, open-label, BREAKWATER trial (NCT04607421), in which the confirmed objective response rate (ORR) was 61% (95% CI, 52%-70%) in the encorafenib/cetuximab/mFOLFOX6 arm compared with 40% (95% CI, 31%-49%) in a control arm. The median duration of response was 13.9 months (95% CI, 8.5-not estimable) and 11.1 months (95% CI, 6.7-12.7), respectively.

To be eligible for enrollment on BREAKWATER, patients must have had treatment-naive, BRAF V600E mutation–positive mCRC. In the study, patients were initially randomized 1:1:1 to one of the following treatment arms:

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

The study was later amended to limit randomization to a 1:1 design instead, which encompassed the encorafenib/cetuximab/mFOLFOX6 arm and the control arm. Treatment was administered until disease progression, acceptable toxicity, lost to follow-up, consent withdrawal, or death.

The primary efficacy outcome measure was confirmed ORR, assessed by blinded independent central review and evaluated in the first 110 patients randomized in each arm.

Regarding safety, the most common adverse effects (AEs) occurring in at least 25% of patients were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia. The most common grade 3/4 laboratory abnormalities in at least 20% of patients were increased lipase and decreased neutrophil count.

Recommended dosage for encorafenib is 300 mg in four 75-mg capsules taken orally once daily in combination with cetuximab and mFOLFOX6 until disease progression or unacceptable toxicity.

Progression-free survival and overall survival in the ongoing BREAKWATER trial is being evaluated and will serve as post-marketing confirmatory evidence for the accelerated approval.

Reference

1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. December 20, 2024. Accessed December 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf