Drug Combos Validated in BRAF-Mutant Melanoma

Combination therapy is likely to become the standard of care for patients with advanced or metastatic melanoma with BRAF mutations, according to three phase III studies presented or published during the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain, in September.

The studies show that combining BRAF and MEK inhibitors improves progression-free survival (PFS) and overall survival (OS), compared with BRAF inhibition alone, in patients with metastatic melanoma with BRAF V600E or V600K mutations. Simultaneous inhibition of BRAF and MEK also can mitigate the emergence of resistance and reduce toxicities associated with BRAF inhibitors.

“Whereas the earlier studies demonstrated that response rates were higher and more durable with the combination, now we have conclusive evidence that patients who take the combination therapy live longer,” says Antoni Ribas, MD, PhD, a hematologist/oncologist and professor of medicine at Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. “At the same time, when you put these two classes of drugs together, it decreases the main toxicity of BRAF inhibitors alone, which is the development of secondary squamous cell carcinomas.”

Up to a quarter of patients treated with BRAF inhibitors develop new skin cancers due to “paradoxical” activation of the MAPK pathway with upstream activation of signaling by preexisting RAS mutations. MEK inhibitors can block RAS signaling along the MAPK pathway.

In the COMBI-v study, presented at ESMO, 704 patients were randomly assigned to receive first-line therapy with the BRAF inhibitor dabrafenib [Tafinlar; GlaxoSmithKline (GSK)] plus the MEK inhibitor trametinib (Mekinist; GSK), or the BRAF inhibitor vemurafenib (Zelboraf; Genentech) alone. The study was stopped early after patients receiving the combination experienced significantly longer OS than patients given the single agent (median OS not reached vs. 17.2 months), as well as higher PFS (11.4 vs. 7.3 months) and duration of response (13.8 vs. 7.5 months).

The COMBI-d study, published in The New England Journal of Medicine (NEJM), demonstrated that dabrafenib plus trametinib given as first-line therapy resulted in a 25% relative reduction in the risk of disease progression compared with dabrafenib alone, as well as a higher response rate (67% vs. 51%; N Engl J Med 2014 September 29 [Epub ahead of print]).

In the third study, coBRIM, also presented at ESMO and published in NEJM, 495 previously untreated patients were randomly assigned to receive vemurafenib either with the MEK inhibitor cobimetinib (GDC-0973; Roche) or with placebo. Combination therapy resulted in improved PFS compared with the control group (9.9 months vs. 6.2 months) and a higher 9-month OS rate (81.1% vs. 72.5%; N Engl J Med 2014 September 29 [Epub ahead of print]).

Earlier this year, the FDA granted accelerated approval of GSK's dabrafenib–trametinib combination for melanoma patients with the BRAF V600 mutation, based on results from phase II studies. COMBI-v and COMBI-d validate that approval, says Ribas, and, along with coBRIM, pave the way for developing other BRAF–MEK combinations.

“BRAF–MEK inhibition is a very elegant combination that slows tumor activity while decreasing the main side effect of the single agent,” says Ribas. “With these new data, there is no reason to consider starting a patient with BRAF mutation–positive melanoma on single-agent therapy.”

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