First-line Combination Therapy for BRAF-mutated Metastatic Colorectal Cancer
The FDA approved the kinase inhibitors encorafenib and cetuximab plus chemotherapy for the treatment of certain colorectal cancers.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to encorafenib (Braftovi), in combination with cetuximab (Erbitux) and the chemotherapy regimen mFOLFOX6, for the treatment of patients with metastatic colorectal cancer that harbors a BRAF V600E mutation.
Encorafenib and cetuximab are targeted therapies that block the cell signaling proteins BRAF and EGFR, respectively. Both BRAF and EGFR work in a signaling pathway that stimulates cell proliferation. The BRAF V600E mutation can cause BRAF to signal uncontrollably, contributing to cancer growth. Blocking both BRAF and EGFR can inhibit this growth by shutting down the pathway. Because upregulating EGFR is also a common way tumors develop resistance to BRAF inhibitors, blocking both may also help prevent resistance. mFOLFOX6 is a combination chemotherapy regimen consisting of leucovorin, 5-fluorouracil, and oxaliplatin.
The combination of encorafenib and cetuximab was previously approved for patients with metastatic colorectal cancer who had already undergone previous treatments. The current approval establishes encorafenib, cetuximab, and mFOLFOX6 as an option for the first-line treatment of these patients. The preclinical efficacy of this regimen was demonstrated in a study published in the AACR journal Clinical Cancer Research.
The approval was based on results from the active-controlled, open-label, multicenter phase III BREAKWATER clinical trial. The researchers recruited patients with untreated, BRAF V600E-mutated metastatic colorectal cancer and randomly assigned them (1:1:1) to receive encorafenib plus cetuximab, encorafenib plus cetuximab and mFOLFOX6, or a control regimen of bevacizumab (Avastin) with or without chemotherapy. The encorafenib plus cetuximab arm was discontinued early, and randomization continued (1:1) in the remaining two arms.
Among the first 110 patients assigned to each arm, 61% experienced a response lasting a median of 13.9 months in the encorafenib, cetuximab, and mFOLFOX6 arm, and 40% experienced a response lasting a median of 11.1 months in the control arm.
The prescribing information for cetuximab contains a boxed warning for severe infusion reactions and cardiopulmonary arrest.
The recommended dose of encorafenib is 300 mg orally once daily until disease progression or unacceptable toxicity. The recommended dose of cetuximab is 400mg/m2 for the first infusion and 250 mg/m2 weekly for subsequent infusions until disease progression or unacceptable toxicity.
Colorectal cancer is a cancer that forms in the large intestine or rectum. Around 10% of metastatic colorectal cancers are estimated to harbor the BRAF V600E mutation. According to federal statistics, it was estimated that 152,810 individuals would be diagnosed with colorectal cancer and 53,010 patients would die of the disease in the United States in 2024.
The FDA rendered its decision on December 20, 2024. Accelerated approval means that continued approval may be contingent upon a confirmatory trial. Please check this FDA web page for information about any accelerated approvals in oncology that may have been subsequently withdrawn and are no longer FDA-approved. Check this resource for updated information on all therapeutics regulated by the FDA.
