FDA Approval for Trametinib
Brand name(s): Mekinist
- Approved for unresectable or metastatic melanoma with BRAF V600E or V600K mutation
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On May 29, 2013, the Food and Drug Administration (FDA) approved trametinib (Mekinist tablet, GlaxoSmithKline, LLC), for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E or V600K mutation as detected by an FDA-approved test. Concurrent with this approval, FDA approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAFV600E and BRAFV600K mutations. Trametinib is not indicated for treatment of patients who have received prior BRAF inhibitor therapy.
Trametinib approval was based on the demonstration of an improved progression-free survival (PFS) in a multi-center international open-label randomized (2:1), active-controlled trial that enrolled 322 patients with histologically confirmed stage IIIc or IV melanoma determined to be BRAFV600E or V600K mutation-positive based upon centralized testing. No more than one prior chemotherapy regimen was permitted. Patients with prior exposure to BRAF inhibitors or MEK inhibitors were ineligible.
Patients were randomly assigned to receive either trametinib 2 mg orally once daily (n=214) or chemotherapy consisting of either dacarbazine or paclitaxel administered intravenously every three weeks (n= 108). At the time of disease progression, 51 patients (47 percent) who had been randomly assigned to chemotherapy received trametinib.
Of the 322 patients enrolled in the trial, 54 percent were male, the median age was 54 years, all had baseline ECOG performance status of 0 or 1, and 64 percent had M1c disease. All patients had tumor tissue with the BRAFV600E mutation (87 percent), the BRAFV600K mutation (12 percent), or both mutations (less than 1 percent) on centralized testing.
A statistically significant prolongation of investigator-assessed PFS was demonstrated for patients randomly assigned to receive trametinib compared with those randomly assigned to receive chemotherapy [HR 0.47 (95 percent CI: 0.34, 0.65); p < 0.0001, log-rank test]. The median PFS was 4.8 months for patients who received trametinib and 1.5 months for patients who received chemotherapy. A PFS analysis that was assessed by blinded independent central review was consistent with the investigator results.
The investigator-assessed objective response rates were 22 percent (95 percent CI: 17, 28) for patients treated with trametinib and 8 percent (95 percent CI: 4, 15) for patients treated with chemotherapy. The analysis of overall survival was not mature.
There was no evidence of antitumor activity with trametinib in patients who had received prior BRAF inhibitor therapy. This was evaluated in a single-arm multicenter international trial enrolled 40 patients with BRAFV600E or V600K mutation-positive unresectable or metastatic melanoma, all of whom had received prior treatment with a BRAF inhibitor. None of these 40 patients achieved a confirmed partial or complete response, as determined by the clinical investigators.
Serious adverse drug reactions occurring in patients taking trametinib included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin toxicity.
The recommended dose and schedule for trametinib is 2 mg orally once daily, continued until disease progression or unacceptable toxicity. Trametinib should be taken at least one hour before or two hours after a meal.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products, or Patricia Keegan, M.D., director of the FDA's Division of Clinical Trials Design and Analysis.
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