The U.S. Food and Drug Administration (U.S.FDA) has approved trametinib (Mekinist?; Glaxosmithkline/GSK) for use in combination with dabrafenib (Tafinlar?;Glaxosmithkline/GSK) for the treatment of patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations. These mutations must be detected by an FDA-approved companion test. Dabrafenib is not indicated for treatment of patients with wild-type BRAF melanoma.
The approval of the combination is based on the demonstration of response rate and median duration of response in a Phase I/II study. Improvement in disease-related symptoms or overall survival has not been demonstrated for trametinibin combination with dabrafenib.
This is first approved combination of targeted therapies in metastatic melanoma, 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 combination was approved through the FDA’s Accelerated Approval programme and reviewed under a Priority Review designation. This accelerated approval is contingent on the results of the ongoing Phase III 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,” noted Paolo Paoletti, M.D., President of Oncology at GSK. “This is first approved combination of targeted therapies in metastatic melanoma, 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 randomised Phase II part of the Phase I/II open-label study, which evaluated the combination of trametinib and dabrafenib at the recommended dose (150/2mg) (N=54) and single-agent dabrafenib (150mg) (N=54)1, were as follows:
- The investigator-assessed overall response rate (ORR) (main efficacy endpoint) was 76% (95% CI, 62, 87) for patients treated with the combination, and 54% (95% CI, 40, 67) for patients treated with single-agent dabrafenib.
- The median duration of response was 10.5 months (95% CI, 7, 15) for patients treated with the combination, and 5.6 months (95% CI, 5, 7) 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% (95% CI, 43, 71) for patients treated with the combination, and 46% (95% CI, 33, 60) for patients receiving single-agent dabrafenib.
- The median duration of response as assessed by the IRRC was 7.6 months (95% CI, 7, NR) for patients treated with the combination, and 7.6 months (95% CI, 6, NR) for patients treated with single-agent dabrafenib.
Trametinib was in-licensed by GSK in 2006. GSK holds the worldwide exclusive rights to develop, manufacture and commercialise Mekinist, while Japan Tobacco retains co-promotion rights in Japan.
For more information
 Glaxosmithkline. Mekinist Prescribing Information 2014.
 GlaxoSmithKline. Tafinlar Prescribing Information 2013.
 U.S. Food and Drug Administration. Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. Accessed December 10, 2013. [FDA Site]
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