Encorafenib with cetuximab and mFOLFOX6 is approved by the USFDA for metastatic colorectal cancer with a BRAF V600E mutation

On December 20, 2024, the Food and Drug Administration conferred accelerated approval for encorafenib (Braftovi, Array BioPharma Inc., a subsidiary of Pfizer Inc.) in conjunction with cetuximab and mFOLFOX6 for patients diagnosed with metastatic colorectal cancer (mCRC) harboring a BRAF V600E mutation, as identified by an FDA-sanctioned assay.

Effectiveness and Safety

The efficacy was assessed in the BREAKWATER trial (NCT04607421), which was an active-controlled, open-label, multicenter study. Patients were mandated to possess treatment-naïve BRAF V600E mutation-positive metastatic colorectal cancer, identified using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit. Patients were first randomized in a 1:1:1 ratio to one of the subsequent treatment arms:

Encorafenib administered orally once daily in conjunction with cetuximab via IV infusion biweekly (encorafenib+cetuximab arm), encorafenib orally once daily combined with cetuximab IV infusion biweekly and mFOLFOX6 biweekly (encorafenib+cetuximab+mFOLFOX6 arm), or mFOLFOX6, FOLFOXIRI (both biweekly) or CAPOX (every three weeks), each with or without bevacizumab (control arm).

The trial was then modified to restrict randomization (1:1) to the encorafenib + cetuximab + mFOLFOX6 group and the control group. Treatment in all groups persisted until disease progression, intolerable toxicity, withdrawal of consent, loss to follow-up, or death. The outcomes of the encorafenib + cetuximab + mFOLFOX6 regimen in comparison to the control group constituted the foundation for this expedited approval and are detailed below.

The primary efficacy outcome measure was the confirmed objective response rate (ORR), assessed through blinded independent central review, and evaluated in the first 110 patients randomized in each group. The overall response rate (ORR) was 61% (95% CI: 52%, 70%) in the encorafenib plus cetuximab and mFOLFOX6 group, compared to 40% (95% CI: 31%, 49%) in the control arm. The median duration of response (DoR) was 13.9 months (95% CI: 8.5, not estimable) and 11.1 months (95% CI: 6.7, 12.7) in the respective groups.

The assessment of progression-free survival and overall survival in the ongoing BREAKWATER study will provide post-marketing confirmatory evidence for this accelerated approval. This program exemplifies the Oncology Center of Excellence’s Project FrontRunner, which seeks to advance significant medicines to earlier stages of disease.

The predominant adverse effects (≥25%) included peripheral neuropathy, nausea, fatigue, rash, diarrhea, diminished appetite, vomiting, bleeding, abdominal discomfort, and pyrexia. The predominant Grade 3 or 4 laboratory abnormalities (≥20%) were elevated lipase levels and reduced neutrophil count.

The advised dosage of encorafenib is 300 mg (four 75 mg capsules) used orally once a day in conjunction with cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) until disease progression or intolerable toxicity occurs. The whole dosing information is available in the prescribed information.