Rare Disease Report

FDA Grants Full Approval of Melanoma Combination Therapy Based on Phase 3 Data

NOVEMBER 20, 2015
James Radke, PhD
The FDA has granted full approval of the combination Tafinlar (dabrafenib) + Mekinist (trametinib) for the treatment of patients with BRAF V600E/K mutation-positive unresectable or metastatic BRAF-mutated melanoma.
Tafinlar is a BRAF inhibitor while Mekinist is a MEK1/2 inhibitor.
The combination was initially approved in 2014 based on Phase 2 data through the FDA’s Accelerated Approval program and reviewed under a Priority Review designation. The approval was contingent on the results of the Phase3 COMBI-d study (see below). The combination was also granted orphan drug designation.

Safety and Efficacy – Phase 3 Studies

COMBI-d was a pivotal Phase 3, randomized, double-blinded study that compared the combination Tafinlar and Mekinist to Tafinlar and placebo in patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The primary endpoint of this study was investigator-assessed progression-free survival. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and safety.
Updated results from the COMBI-d study showed that the combination of Tafinlar + Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months vs 18.7 months; HR 0.71 [95% CI, 0.55-0.92], p=0.01). The analysis for the combination also showed median PFS of 9.3 months compared to 8.8 months for those who received Tafinlar only; HR 0.75 [95% CI, 0.57-0.99, p=0.035].  ORR was 66% [95% CI, 60, 73] compared to 51% [95% CI, 44, 58] for those in the Tafinlar + Mekinist group and the Tafinlar only group, respectively. Median DoR was 9.2 months [95% CI, 7.4, not reached] compared to 10.2 months [95% CI, 7.5, not reached] for those receiving the combination of Tafinlar + Mekinist compared to those who received Tafinlar only, respectively.
A second phase 3 study, COMBI-v, was a two-arm, open-label, Phase 3 study that compared the combination of Tafinlar + Mekinist with vemurafenib monotherapy in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. The primary endpoint of this study was OS. The study was stopped tearly based on efficacy results observed in the Tafinlar + Mekinist study arm as part of a planned interim analysis. Results from the study showed that the combination of Tafinlar + Mekinist significantly improved OS compared to vemurafenib monotherapy. At the time the data were submitted to the FDA for approval, median OS had not yet been reached in the combination therapy arm and was 17.2 months in the vemurafenib arm. Median PFS was 11.4 months vs 7.3 months for the Tafinlar + Mekinist arm compared to the vemurafenib arm; HR 0.56 [95% CI, 0.46-0.69, p<0.001]. ORR was 64% [95% CI, 59, 69] in the Tafinlar + Mekinist arm and 51% in the vemurafenib arm [95% CI, 46, 56] and median DoR was 13.8 months for the Tafinlar + Mekinist combination [95% CI, 11.0 to not reached] and 7.5 months in the vemurafenib arm [95% CI, 7.3 to 9.3].
Pooled safety data from the COMBI-d and COMBI-v trials show the most common adverse events reported with Tafinlar + Mekinist (greater than or equal to 20%) were pyrexia, nausea, rash, chills, diarrhea, headache, vomiting, hypertension, joint pain (arthralgia), peripheral edema, and cough. The most common Grade 3/4 adverse reactions (greater than or equal to 2%) were hypertension, pyrexia, and hemorrhage. In COMBI-d, 11% of patients receiving the combination discontinued the combination due to an adverse reaction.

Melanoma is the most aggressive and dangerous form of skin cancer in the United States. The National Cancer Institute estimates that 73,870 Americans will be diagnosed with melanoma and 9,940 will die from the disease this year.

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