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FDA Approves Mekinist/Tafinlar Combo in Advanced, BRAF-mutated Melanoma

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Originally published Jan. 14.

The US Food and Drug Administration last week granted accelerated approval to a combination of two personalized drugs, Mekinist (trametinib) and Tafinlar (dabrafenib), as a new option for melanoma patients with advanced, unresectable, or metastatic disease who harbor BRAF mutations.

The regimen is the first FDA-approved combination treatment for melanoma.

Specifically, the BRAF inhibitor Tafinlar treats melanoma patients whose tumors have BRAF V600E mutations. Mekinist, a MEK inhibitor, is indicated to treat patients who express the BRAF V600E or V600K mutations. Last year, the agency approved these two drugs, developed by GlaxoSmithKline, as single agents that treat BRAF mutated melanoma patients whose tumors have spread or cannot be removed with surgery.

When the agency approved these drugs in May 2013, it also approved BioMérieux's THxID BRAF Kit as a companion diagnostic that doctors can use to identify best responders to treatment. The Mekinist/Tafinlar combination regimen is indicated for melanoma patients with tumors that have BRAF V600E or V600K mutations, both of which BioMérieux's test gauges.

The NCI estimates that in 2013 nearly 77,000 patients were diagnosed with melanoma and 9,500 died from the disease. Approximately 50 percent of melanoma patients harbor BRAF mutations, which drive the growth of cancer cells.
 
The development of the Mekinist/Tafinlar combination “is based on the strong understanding of the biological pathways of the disease,” Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, said in a statement. “This approval illustrates the value of continuing to study drugs in combination for clinical development.”

The FDA granted GSK approval for the combination regimen based on data from a clinical trial involving 162 patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. These patients, most of whom had received prior therapy, received either Mekinist and Tafinlar or just Tafinlar until their disease progressed or they could no longer tolerate the side effects.

In the study, 76 percent of the patients treated with the combination regimen saw their tumors shrink or disappear, an effect that lasted an average of 10.5 months. Comparatively, 54 percent of those who received just Tafinlar had an objective response for average of 5.6 months. As the trial is ongoing, researchers are following patients to see if the Mekinist/Tafinlar combo improves their survival compared to single agent Tafinlar.

Since the Tafinlar/Mekinist regimen was approved by the FDA under the accelerated approval pathway, GSK could provide data showing that the treatment had an effect on a surrogate endpoint, such as objective response. Additionally, the FDA noted that the Mekinish/Tafinlar regimen was also granted under the agency's priority review pathway because it promised to significantly improve treatment of a serious condition.
 
Patients treated with Mekinist and Tafinlar in the study experienced common side effects, such as fever, chills, tiredness, rash, nausea, vomiting, swelling of the hands and feet, as well as serious side effects such as bleeding, clot formation, heart failure, and skin and eye problems. In the study, patients had more frequent and severe fever with the combination regimen compared to single agent Tafinlar.

“One of the serious side effects of Tafinlar — the development of a new squamous cell carcinoma of the skin — was reduced when the drug was used in combination with Mekinist,” the agency stated. “This is consistent with the biology of the effects of these two drugs on the targeted molecular pathway.” In the combination treatment arm, 7 percent had squamous cell carcinoma versus 19 percent in the Tafinlar-only arm.
 
The drugs can cause birth defects in a developing fetus, the agency warned women of childbearing age in approving the treatments. The FDA also cautioned patients that Tafinlar and Mekinist could cause infertility.

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