Combination BRAF, MEK Inhibition "New Standard" for Previously Untreated BRAF-Mutant Melanoma

Grant McArthur, MD

Inhibiting BRAF and MEK at the same time improves progression-free survival (PFS) more so than BRAF inhibition alone in patients with BRAF V600 mutation-positive metastatic melanoma, according to results of a phase III placebo-controlled trial.

The most common mechanism of acquired resistance to the BRAF inhibitor vemurafenib is reactivation of cell growth of the MAPK pathway through MEK. Using a BRAF inhibitor and MEK inhibitor together in the first-line setting turns off the two individual proteins, preventing their interaction and delaying development of resistance that is observed with BRAF inhibition alone, said Grant McArthur, MD, lead investigator of the study. BRAF V600 mutations occur in about 40% of patients with melanoma, he said.

“We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma,” he said. McArthur presented the study results at the 2014 ESMO Congress.

MEK plus BRAF inhibition had previously been shown to improve response rates and PFS in BRAF inhibitor—naïve melanoma patients in early- and late-phase clinical trials. The incidence of hyperproliferative lesions has also been reduced by blocking paradoxical activation of the MAPK pathway from RAF inhibition (Lancet Oncol. 2014;15(9):954-965).

The MEK inhibitor cobimetinib used in the study is a small molecule that is an extremely selective allosteric inhibitor of MEK, McArthur said.

In the ongoing coBRIM study, 495 treatment-naive patients with BRAF V600-mutation-positive unresectable locally advanced or metastatic melanoma were randomized in a 1:1 ratio to the combination of vemurafenib and the MEK inhibitor cobimetinib or vemurafenib and placebo. Vemurafenib was administered at 960 mg twice daily for a 28-day cycle. Cobimetinib or placebo was administered at 60 mg/day from days 1 to 21 of the 28-day cycle.

After a median follow-up of more than 7 months in both arms, investigator-assessed median PFS, the primary endpoint, was superior with combination therapy. There were 79 PFS events in the combination arm versus 128 such events in the vemurafenib plus placebo arm. Patients randomized to vemurafenib plus cobimetinib had a median PFS of 9.9 months, compared with 6.2 months for patients assigned to vemurafenib plus placebo. The difference translated into a hazard ratio (HR) of 0.51 for risk of progression in favor of the combination (P <.0001). The PFS benefit to combination therapy was similar when the PFS events were reviewed independently (HR = 0.60; P =.0003).

Objective response rates were 68% in the combination arm and 45% in the vemurafenib plus placebo arm (P <.0001). Complete responses occurred in 10% of combination therapy recipients compared with 4% of patients randomized to vemurafenib plus placebo, said McArthur, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Center in Melbourne, Australia.

An interim analysis of overall survival (OS) showed 51 deaths in the vemurafenib monotherapy arm compared with 34 deaths in the combination therapy arm, corresponding to a 35% reduction in the risk of death (HR = 0.65; P <.046) with combination therapy. Because the interim OS analysis did not pass the prespecified boundary for significance for an OS benefit, coBRIM is ongoing to evaluate mature OS rates.

The adverse event profile of the combination was “tolerable and manageable,” and consistent with previous trials of the combination, said McArthur. Gastrointestinal (GI) adverse events (diarrhea, nausea, vomiting) were more frequent with the combination compared with vemurafenib monotherapy. The GI events were mostly grade 1 and grade 2, occurred early in the study, and did not cause discontinuation of study drugs.

The rate of grade ≥3 adverse events was greater with the BRAF/MEK combination versus vemurafenib alone (65% vs 59%), but there was no difference in the rate of adverse events that led to study drug discontinuation, and adding cobimetinib reduced the rate of secondary cutaneous malignancies. In particular, combination therapy reduced the rate of cutaneous squamous cell carcinoma from 11% to 3%, and the rate of keratoacanthoma from 8% to 1%.

“Serous retinopathy and decreased ejection fraction are known toxicities of MEK inhibitors. All patients in this study had regular ophthalmologic review and regular performance of estimation of their left ventricular ejection fraction,” McArthur noted. “Because these are MEK-related toxicities, they are more frequent in the cobimetinib arm.” In the combination arm, 20% of patients had serious retinopathy and 7% had decreased ejection fraction, compared with <1% and 3%, respectively, in the vemurafenib monotherapy arm. Both retinopathy and decreased ejection fraction in the cobimetinib arm were reversible.

McArthur said that the results “are very important because we’re comparing a very active drug for melanoma and adding a second drug on, and still we’re getting quite striking results.”

McArthur G, Ascierto P, Larkin J, et al. Phase 3 double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519). Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. Abstract LBA5.

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