FDA accelerates approval of encorafenib combo for BRAF V600E mutant colorectal cancer

On December 20, 2024, the Food and Drug Administration (FDA) granted accelerated approval to a new treatment regimen for patients with metastatic colorectal cancer (mCRC) characterized by a BRAF V600E mutation. The approved regimen includes the combination of encorafenib (Braftovi, Array BioPharma Inc., a subsidiary of Pfizer Inc.), cetuximab, and mFOLFOX6. This decision marks a significant step forward in targeted cancer therapy, providing a new option for this particular subset of mCRC patients.

The efficacy of this treatment was evaluated in the BREAKWATER trial, an open-label, multicenter study (NCT04607421). The participants were specifically patients with treatment-naïve mCRC with the BRAF V600E mutation, identified using the Qiagen therascreen BRAF V600E RGQ PCR kit. Initially, patients were randomized into three groups: one receiving encorafenib with cetuximab, one receiving encorafenib with cetuximab and mFOLFOX6, and a control group receiving standard chemotherapy regimens such as mFOLFOX6, FOLFOXIRI, or CAPOX, with or without bevacizumab. However, the trial was later adjusted to focus on two groups: those receiving encorafenib, cetuximab, and mFOLFOX6, and the control group.

The primary measure of efficacy was the confirmed objective response rate (ORR), which was assessed by an independent central review in the first 110 patients in each treatment arm. The ORR was substantially higher in the encorafenib, cetuximab, and mFOLFOX6 group at 61%, compared to 40% in the control group. Additionally, the median duration of response (DoR) favored the experimental group, with a median of 13.9 months, compared to 11.1 months in the control.

This accelerated approval was granted based on these encouraging results, although further evaluation of progression-free survival and overall survival is ongoing in the BREAKWATER trial. The findings will serve as confirmatory evidence in the post-marketing phase of this new treatment's approval. This application is part of the FDA's Oncology Center of Excellence’s Project FrontRunner initiative, which aims to expedite the availability of promising therapies for earlier stages of disease.

The treatment was not without side effects. Common adverse reactions in patients receiving the approved combination included peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and fever. Laboratory tests also revealed increased lipase levels and decreased neutrophil counts as common grade 3 or 4 abnormalities.

For the new regimen, the recommended dosage for encorafenib is 300 mg (four 75 mg capsules) taken orally once daily alongside cetuximab and mFOLFOX6 (comprising fluorouracil, leucovorin, and oxaliplatin) until the disease progresses or unacceptable toxicity is reached. Detailed prescribing information will be available for healthcare professionals.

The approval process for this combination therapy utilized the FDA's Project Orbis, which allows for the simultaneous submission and review of oncology drugs by international regulatory bodies. In this instance, the FDA worked alongside Health Canada. The process was further expedited by employing the Real-Time Oncology Review (RTOR) pilot program, which allows for early data submission, and the Assessment Aid, a voluntary submission tool designed to facilitate the FDA's review process.

This application received priority review status, underscoring its potential impact on a serious health condition. Healthcare professionals are encouraged to report any serious adverse events related to this treatment, as part of ongoing safety monitoring efforts.