GSK wins accelerated FDA approval for combination therapy

LONDON—GlaxoSmithKline plc (GSK) recently announced in a press statement that the U.S. Food and Drug Administration (FDA) has approved Mekinist (trametinib) for use in combination with Tafinlar (dabrafenib) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. In 2010, GSK entered a collaboration with bioMérieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma, and it’s this test that has now been FDA-approved for use with this drug combination.

FDA’s approval of the combination therapy—coupled to the proviso that the BRAF mutations must be confirmed by a FDA-approved companion diagnostic assay—came after the agency’s mid-year approval of both Tafinlar and Mekinist as single agents for treatment for unresectable melanoma in adult patients with the BRAF V600E mutation. Tafinlar is not indicated for the treatment of patients with wild-type BRAF melanoma. Mekinist is indicated as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. The BRAF V600E mutation accounts for approximately 85 percent of all BRAF V600 mutations in metastatic melanoma. Mekinist is also approved for patients with the V600K mutation, which makes up approximately 10 percent of all BRAF V600 mutations in metastatic melanoma.

“With today’s FDA approvals, GSK can now offer two new single-agent therapies to selected patients who have metastatic melanoma, a devastating disease with very low survival rates and few treatment options,” Dr. Paolo Paoletti, president of oncology at GSK, said at the time of the monotherapy approvals.

The approval of the combination treatment is based on the demonstration of response rate and median duration of response in a Phase 1/2 study. Improvement in disease-related symptoms or overall survival has not been demonstrated for Mekinist in combination with Tafinlar. The combination was approved through the FDA’s Accelerated Approval program and reviewed under a Priority Review designation. This accelerated approval is contingent on the results of the ongoing Phase 3 trial (referred to as MEK115306 or Combi-D), which is designed to evaluate the clinical benefit of the combination in this patient population.

“This approval marks another key moment in what continues to be a rapid evolution of the treatment landscape for metastatic melanoma patients. Combining agents that target different mechanisms regulating the growth of cancer cells is one of the promising areas in cancer research,” said Paoletti. “We are proud that the first approved combination of targeted therapies in metastatic melanoma is Mekinist and Tafinlar, and our hope is that it will become part of the new standard of care for appropriate patients with BRAF V600E or V600K mutation-positive metastatic melanoma.”

The results from the randomized Phase 2 part of the Phase 1/2 open-label study, which evaluated the combination of trametinib and dabrafenib at the recommended dose (150/2mg) and single-agent dabrafenib (150mg) demonstrated that the investigator-assessed overall response rate (ORR), which was the main efficacy endpoint, was 76 percent for patients treated with the combination, and 54 percent for patients treated with single-agent dabrafenib. The median duration of response was 10.5 months for patients treated with the combination, and 5.6 months for patients treated with single-agent dabrafenib.

Data analyses of the blinded independent radiologic review committee (IRRC) supported the investigator results. The IRRC-assessed ORR was 57 percent for patients treated with the combination, and 46 percent for patients receiving single-agent dabrafenib. The median duration of response as assessed by the IRRC was 7.6 months for patients treated with the combination, and 7.6 months for patients treated with single-agent dabrafenib.

“MEK [inhibitors have] been pursued as a therapeutic target in cancer for more than a decade,” said Dr. Keith Flaherty, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center and principal investigator of the Phase 3 METRIC trial. “Based on the clear improvement versus chemotherapy in progression-free survival, trametinib represents the first validated MEK inhibitor. We welcome it as a new treatment option for patients with this disease.”