FDA

Encorafenib combo approved for BRAF V600E mutation-positive colorectal cancer

December 25, 2024

Brand name: Braftovi

Generic name: encorafenib

Manufacturer: Pfizer

Approval date: December 20, 2024

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

Efficacy

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

• encorafenib PO once daily with cetuximab IV infusion q2wks (encorafenib + cetuximab arm)
• encorafenib PO once daily with cetuximab IV infusion q2wks and mFOLFOX6 q2wks (encorafenib + cetuximab + mFOLFOX6 arm)
• mFOLFOX6, FOLFOXIRI (both q2wks) or CAPOX (q3wks) - 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 with the control arm served as the basis of the accelerated approval.

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 vs. 40% (95% CI, 31%, 49%) in the control arm. Median duration of response 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.

Safety

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 lab abnormalities (≥20%) were increased lipase and decreased neutrophil count.

Recommended dose

The recommended dosage of encorafenib 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.

Sources:

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

Pfizer. (2024, December 20). U.S. FDA Approves Pfizer’s BRAFTOVI Combination Regimen as First-Line Treatment of BRAF V600E-Mutant Metastatic Colorectal Cancer. [Press release]. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-braftovir-combination-regimen-first

Pfizer: Breftovi (encorafenib). [Package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/210496s017lbl.pdf