Outcomes in BRAF-Mutant Melanoma Improved With BRAF, MEK Inhibition

The combination of the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib yielded improved progression-free survival over vemurafenib in a phase III trial of patients with advanced BRAF V600–mutant melanoma.

BRAF V600 mutations occur in 35% to 50% of patients with melanoma. Earlier studies have shown that combining a BRAF inhibitor with a MEK inhibitor can potentially improve efficacy and ameliorate the toxic side effects of BRAF inhibition. “Promising clinical activity and tolerability of the combination of encorafenib and binimetinib has been seen in patients with BRAF V600–mutated melanoma in a phase Ib/II and a phase II study,” wrote study authors led by Reinhard Dummer, MD, of the University Hospital Zurich in Switzerland.

The COLUMBUS trial was a randomized, open-label, phase III trial that took place in 28 countries. It included a total of 577 patients randomized to receive either encorafenib plus binimetinib (192 patients), encorafenib alone (194 patients), or vemurafenib alone (191 patients). All those included had locally advanced, unresectable, or metastatic melanoma, with a BRAF V600 mutation and an ECOG performance status of 0 or 1. The median follow-up period was 16.6 months; results were published in Lancet Oncology.

The median progression-free survival was 14.9 months in the combination therapy group, compared with 9.6 months with encorafenib monotherapy and 7.3 months with vemurafenib. The combination group had a lower risk of progression or death compared with the vemurafenib group, with a hazard ratio of 0.54 (95% CI, 0.41–0.71; P < .0001). Subgroup analyses showed benefit with the combination in all groups, with the exception of those with brain metastases at baseline, though this included a total of only 12 patients.

A confirmed response was reported in 63% of the encorafenib-plus-binimetinib group, compared with 51% of the encorafenib group and 40% of the vemurafenib group.

Fewer patients in the combination group reported grade 3/4 adverse events than in either of the other groups, at 58% compared with 66% in the encorafenib group and 63% of the vemurafenib patients. The most common such adverse events seen in more than 5% of patients in the combination group included increased γ-glutamyltransferase (9%), increased creatine phosphokinase (7%), and hypertension (6%). In the encorafenib monotherapy group, these included palmoplantar erythrodysesthesia syndrome (14%), myalgia (10%), and arthralgia (9%); in the vemurafenib group, the only such adverse event was arthralgia (6%). Fewer patients in the combination group had adverse events that led to discontinuation, and serious events occurred at similar rates in the three groups (34%, 34%, and 37%, respectively).

“Encorafenib plus binimetinib represents a new treatment option for patients with BRAF-mutant melanoma, and further studies investigating the optimal sequence of available treatment modalities are underway,” the authors concluded.