The US Food and Drug Administration (FDA) approved the combination of encorafenib (Braftovi, Array BioPharma) and binimetinib (Mektovi, Array BioPharma) today for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.
The new approval is based on a randomized, controlled, open-label, multicenter trial in 577 patients with advanced melanoma, known as COLUMBUS (part 1). Patients were randomly assigned (1:1:1) to receive binimetinib plus encorafenib, or encorafenib, or vemurafenib; all were taken daily and used until progression.
The median progression-free survival (PFS), which was the primary outcome, was 14.9 months for patients receiving binimetinib plus encorafenib and 7.3 months for the vemurafenib monotherapy arm (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.41 - 0.71; P < .0001).
The results were published March 22 in Lancet Oncology.
The company also released overall survival (OS) data in a press statement in February 2018.
Treatment with the combination of encorafenib and binimetinib reduced the risk for death compared to treatment with vemurafenib (HR, 0.61; 95% CI, 0.47 - 0.79; P < .001). Median OS was 33.6 months with the combination compared with 16.9 months with vemurafenib alone, according to the company.
The PFS and OS advantages seen to date with the combination compared with monotherapy are "unprecedented" in the field of targeted therapy for melanoma, said Jeffrey Weber, MD, PhD, from the Perlmutter Cancer Center at the NYU Langone Medical Center, New York City, in a Medscape commentary earlier this month. However, he qualified the praise by saying that the results need to "hold up," including once published.
In the data published in March, the median follow-up was 16.6 months. The overall response rates assessed by blinded independent central review were 63% and 40% for the combination and for vemurafenib alone, respectively. Median duration of response was 16.6 months vs 12.3 months, respectively.
The most common (seen in >5% of patients) grade 3 to 4 adverse events in the encorafenib plus binimetinib group were increased γ-glutamyltransferase levels (9%), increased creatine phosphokinase levels (7%), and hypertension (6%); in the encorafenib group they were palmoplantar erythrodysesthesia syndrome (14%), myalgia (10%), and arthralgia (9%); and in the vemurafenib group, it was arthralgia (6%).
Therapy was discontinued because of adverse reactions in 5% of patients receiving the combination; the most common reasons for discontinuation were hemorrhage and headache.
The FDA today also approved the THxID BRAF Kit (bioMérieux) as a companion diagnostic test for these therapeutics.
The recommended doses, which were used in the trial, are binimetinib 45 mg orally twice daily and encorafenib 450 mg orally once daily. The dose used in the trial for vemurafenib was 960 mg twice daily.
Weber has multiple financial relationships with industry, but none with Array BioPharma.
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Cite this: FDA Approves New Targeted Combo Therapy for Melanoma - Medscape - Jun 27, 2018.