Encorafenib, Cetuximab, and mFOLFOX6 Receive FDA Approval for Colorectal Cancer

On December 20, 2024, the US Food and Drug Administration (FDA) approved treatment for patients with metastatic colorectal cancer (mCRC) carrying a BRAF V600E mutation with the following combination: encorafenib (Braftovi, Array BioPharma Inc., a subsidiary of Pfizer Inc.) with cetuximab and mFOLFOX6 through accelerated approval .

In metastatic colorectal cancer, the BRAF V600E mutation is found in approximately 8-12% of cases. This is consistent with BRAF mutations being detected in 5-10% of all colorectal cancer patients. However, BRAF mutations are more common in metastatic disease, and BRAF V600E is the most frequent type.

• Related topic: What Is Encorafenib (Braftovi)? FDA Approval, Licensing in Turkey, and Reimbursement Status

What Does This New Approval Offer?

With the new FDA approval, encorafenib (Braftovi) combined with cetuximab and mFOLFOX6 chemotherapy has, for the first time, been approved for patients with metastatic colorectal cancer (mCRC) as first-line treatment . This represents an important difference from previous approvals, which restricted encorafenib plus cetuximab to previously treated mCRC patients carrying a BRAF V600E mutation .

Comparing the Previous Indication With the New Approval

1. Previous Indications:

   • In 2020, the FDA approved encorafenib combined with cetuximab for patients who had previously received at least one line of systemic treatment for metastatic colorectal cancer carrying a BRAF V600E mutation.
   • This provided an option for patients with advanced or resistant disease but did not cover first-line use.

2. New Approval:

   • Encorafenib combined with cetuximab and mFOLFOX6 chemotherapy (fluorouracil, leucovorin, and oxaliplatin) can now be used for patients starting treatment who are positive for the BRAF V600E mutation.

FDA Approval Based on the BREAKWATER Trial

The effectiveness and safety of encorafenib were evaluated in BREAKWATER , an active-controlled, open-label, multicenter clinical trial. Patients had a mutation confirmed using the Qiagen therascreen BRAF V600E RGQ PCR kit and were BRAF V600E mutation-positive with previously untreated mCRC. Initially, patients were randomized to three treatment arms in a 1:1:1 ratio:

1. Encorafenib (orally once daily) combined with cetuximab (by intravenous infusion every two weeks),
2. Encorafenib (orally once daily), cetuximab (by intravenous infusion every two weeks), and mFOLFOX6 (chemotherapy every two weeks),
3. Control arm: mFOLFOX6 or FOLFOXIRI every two weeks, or CAPOX every three weeks, each with or without bevacizumab.

The trial was later amended to randomize patients only between encorafenib + cetuximab + mFOLFOX6 and the control arm in a 1:1 ratio. In all arms, treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death.

Results

Results from the encorafenib + cetuximab + mFOLFOX6 arm compared with the control arm formed the basis of this accelerated approval and are summarized below:

Key Efficacy Findings

• Objective Response Rate: The objective response rate, assessed by blinded independent central review, was, in the encorafenib + cetuximab + mFOLFOX6 arm, 61% (95% CI: 52%, 70%), compared with 40% (95% CI: 31%, 49%) in the control arm.

• Median Duration of Response: The median duration of response was, respectively, 13.9 months (95% CI: 8.5, not estimable) and 11.1 months (95% CI: 6.7, 12.7).

In the ongoing BREAKWATER trial, evaluation of progression-free survival (PFS) and overall survival will provide postmarketing confirmatory evidence for this accelerated approval.

Adverse Effects

• Most Common Adverse Effects (25% or Higher): Peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and fever.
• Most Common Severe Laboratory Abnormalities (20% or Higher): Increased lipase and decreased neutrophil count.

Recommended Dosage

The recommended dose of encorafenib is 300 mg (four 75 mg capsules) once daily in combination with cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin). Treatment should continue until disease progression or unacceptable toxicity. Full dosing information is provided in the prescribing information.

The Significance of This Approval

• This approval brings targeted treatment for metastatic colorectal cancer carrying a BRAF V600E mutation into an earlier treatment setting. Patients with BRAF-mutated mCRC constitute a subgroup with a less favorable disease course, and this treatment offers new hope for them.

The Situation in Turkey

• Encorafenib (Braftovi) is licensed in Turkey for metastatic colorectal cancer but is not reimbursed.
• This new accelerated FDA approval may not yet affect its licensing or reimbursement status in Turkey.

The approval offers patients with BRAF-mutated mCRC earlier access to more effective treatment options and an innovative approach extending beyond standard chemotherapy.