Encorafenib/Cetuximab/mFOLFOX6 Receives Accelerated Approval for Metastatic Colorectal Cancer With BRAF V600E Mutation
Expert Perspectives · Keira Smith · 2024-12-27
The FDA has granted accelerated approval to encorafenib (Braftovi®, Array BioPharma, Inc.) with cetuximab and mFOLFOX6 (5-fluorouracil/leucovorin/oxaliplatin) for patients with metastatic colorectal cancer (CRC) who have a BRAF V600E mutation, as detected by an FDA-approved test.
Why Is the Approval Important?
“Approximately 10% of patients with metastatic CRC have BRAF mutations, mostly V600E,” wrote Scott Kopetz, MD, PhD, Professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, and coauthors of the BREAKWATER trial (NCT04607421), on which approval was based.
“First-line treatment options for BRAF V600E metastatic CRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in patients with MSI-H tumors. Given the poor prognosis of patients with BRAF V600E metastatic CRC and based on the efficacy and tolerability of encorafenib + cetuximab from the BEACON CRC trial, BREAKWATER is evaluating efficacy and safety of encorafenib + cetuximab ± chemotherapy in treatment-naive patients with BRAF V600E metastatic CRC.”
Investigating the Encorafenib Combination in BREAKWATER
Efficacy was evaluated in the phase 3, active-controlled, open-label, multicenter trial. Eligible patients had treatment-naive BRAF V600E mutation–positive metastatic CRC, detected by the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit. Patients were initially randomized 1:1:1 into three arms:
- Encorafenib + cetuximab arm: encorafenib orally once daily, with a cetuximab intravenous (IV) infusion every two weeks
- Encorafenib + cetuximab + mFOLFOX6 arm: encorafenib orally once daily, with cetuximab IV infusion every 2 weeks and mFOLFOX6 every two weeks
- Control arm: mFOLFOX6 every two weeks, FOLFOXIRI (folinic acid/5-fluorouracil/oxaliplatin/irinotecan) every two weeks, or CAPOX (capecitabine/oxaliplatin) every three weeks; each with or without bevacizumab
Later, the trial was amended to limit randomization (1:1) to two arms: the encorafenib + cetuximab + mFOLFOX6 arm and the control arm, results on the accelerated approval was based. The primary end point was confirmed objective response (ORR) in the first 110 patients randomized in each arm, assessed by blinded independent central review.
The ORR was 61% in the encorafenib + cetuximab + mFOLFOX6 arm compared with 40% in the control arm. The median durations of response were 13.9 months and 11.1 months, respectively.
Adverse Events
The most common adverse events, occurring in ≥25% of patients, were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia. The most common grade 3 or 4 laboratory abnormalities, occurring in ≥20% of patients, were increased lipase and decreased neutrophil count.
Future Directions
Post-marketing confirmatory evidence for the accelerated approved will be based on evaluation of progression-free survival and overall survival in the ongoing BREAKWATER trial.
Dosing Instructions
The recommended dose of encorafenib is 300 mg (four 75-mg capsules) orally once daily, with cetuximab and mFOLFOX6, until disease progression or unacceptable toxicity. Please refer to the prescribing information for full dosing information.