Combination Therapy Approved for Melanoma

In January, the U.S. Food and Drug Administration (FDA) approved the targeted drug combination of trametinib (Mekinist; GlaxoSmithKline) and dabrafenib (Tafinlar; GlaxoSmithKline) for treating patients with metastatic or unresectable melanoma with BRAF V600K or V600E mutations. Both drugs received approval as monotherapies in May 2013.

Trametinib and dabrafenib inhibit kinases in the RAS/RAF/MEK/ERK pathway. In clinical trials, patients treated with either of these single-agent therapies develop resistance to the drugs and have disease progression within 6 or 7 months, but their combined effect extends that time.

Keith Flaherty, MD, an oncologist at the Massachusetts General Hospital Cancer Center in Boston, says combination therapies expand the efficacy of the first generation of targeted drugs, the earliest of which entered treatment regimens more than a dozen years ago.

“Numerous two-drug combinations are being evaluated in ongoing drug trials now,” he says, representing the beginning of a coming wave of multidrug therapies. “I think 2014 will witness the first wave of triplet targeted regimens as well.”

Targeted therapies often benefit only a small fraction of a cancer population, but combination therapies may prolong response times and benefit additional patient subgroups.

In the approval statement, the FDA cited results from a phase II open-label clinical trial, led by Flaherty, involving 162 patients with metastatic melanoma that expressed a BRAF mutation, most of whom were previously untreated. Participants received either dabrafenib alone or dabrafenib in combination with trametinib. Patients who received the highest combination dose—150 mg of dabrafenib twice daily with 2 mg of trametinib once daily—had an objective response rate of 76% and a median progression-free survival (PFS) of 9.4 months, compared with 54% and 5.8 months in patients treated only with dabrafenib. Overall survival data are not yet available.

On January 24, after FDA approval was granted, GlaxoSmithKline announced that the combination met its primary endpoint of PFS in a phase III trial that compared the combination to dabrafenib plus a placebo. PFS, response rate, and interim overall survival results were consistent with those seen in earlier studies, according to the company. Full results will be presented at an upcoming scientific meeting.

When targeted therapy is appropriate for a patient, the newly approved combination clearly has some advantages over single agents and “should be considered as an option for standard of care,” says Mario Sznol, MD, an oncologist at the Yale Cancer Center in New Haven, CT. Data from the phase II trial, which was published in 2012, “really showed a dramatic improvement in progression-free survival for the combination,” with tolerable toxicity.

The next difficult decision clinicians will face, says Sznol, is determining whether to offer the combination targeted therapy or immunotherapy to a patient with a BRAF mutation—or offer both, one after the other.

“We may need a randomized trial to determine which sequence of therapies, if sequencing is indeed the best approach, would lead to the best outcome in the majority of patients.”

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