FDA Grants Accelerated Approval to Encorafenib/Cetuximab/Chemo Combo in BRAF V600E+ mCRC

• The FDA granted accelerated approval to the combination of encorafenib (Braftovi), cetuximab (Erbitux), and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test.
• Findings from the phase 3 BREAKWATER trial (NCT04607421) support this regulatory decision.
• The set recommended dose of encorafenib is 300 mg once daily plus cetuximab and mFOLFOX6 until disease progression or unacceptable toxicity.

The FDA has granted the combination of encorafenib, cetuximab, and mFOLFOX6 accelerated approval for the treatment of patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test.¹

Data from the phase 3 BREAKWATER trial serve as the basis for this regulatory decision as patients treated with the encorafenib, cetuximab, and mFOLFOX6 combination had an overall response rate (ORR) of 61% (95% CI, 52%-70%) vs 40% (95% CI, 31%-49%) among those treated with chemotherapy with or without bevacizumab (Avastin; P =.0008).^1,2 The median duration of response (DOR) was 13.9 months (95% CI, 8.5-not estimable) compared with 11.1 months (95% CI, 6.7-12.7), respectively.

Looking at safety, the most common adverse events seen in at least 25% of patients treated with the experimental combination were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.1 The most common laboratory abnormalities seen in 20% of patients or more and deemed grade 3 or 4 included increased lipase levels and decreased neutrophil counts.

Microscopic image of colorectal cancer cells - Generated with Google Gemini AI

The ongoing BREAKWATER trial will evaluate progression-free and overall survival (OS) as post-marketing confirmatory evidence for this accelerated approval.

Encorafenib is recommended at a daily dose of 300 mg, given alongside cetuximab and mFOLFOX6, until either disease progression or unacceptable toxicity occurs.

About the BREAKWATER Trial

BREAKWATER was a randomized, active-controlled, open-label, multicenter trial which evaluated the combination of encorafenib, cetuximab, and mFOLFOX6 for the treatment of patients with mCRC harboring a BRAF V600E mutation.³ Patients aged 18 years and older were included in the safety run-in portion of the study, and those at least 16 years of age were included in the phase 3 portion.

In the safety run-in portion, patients could have up to 1 prior line of therapy, while in the phase 3 portion, no prior systemic therapy in the metastatic setting was allowed. Further, patients must have had measurable disease for phase 3, measurable or evaluable disease for the safety run-in, an ECOG performance status of 0 to 1, and adequate organ function.

Patients included in the phase 3 portion were randomly assigned in a 1:1:1 fashion to receive oral encorafenib at 300 mg once per day plus cetuximab (n = 158); encorafenib at 300 mg once per day plus cetuximab and mFOLFOX6 (n=236), or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (n = 243).²

The primary end points of the phase 3 portion of the trial included progression-free survival and ORR, and secondary end points were OS, DOR, time to response, and safety.³

REFERENCES

1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed December 23, 2024. https://tinyurl.com/yxnzzp6s

2. U.S. FDA approves Pfizer’s Braftovi combination regimen as first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. News release. Pfizer. December 20, 2024. Accessed December 23, 2024. https://tinyurl.com/3xaza5sy

3. A study of encorafenib plus cetuximab with or without chemotherapy in people with previously untreated metastatic colorectal cancer. ClinicalTrials.gov. Updated December 17, 2024. Accessed December 23, 2024. https://clinicaltrials.gov/study/NCT04607421