On May 29, 2013, the U. S. Food and Drug Administration approved trametinib (MEKINIST tablet, GlaxoSmithKline, LLC), for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E 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 BRAF V600E and V600K mutations. Trametinib is not indicated for treatment of patients who have received prior BRAF inhibitor therapy.
Trametinib’s 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 enrolling 322 patients with histologically confirmed Stage IIIc or IV melanoma determined to be BRAF V600E 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 randomized 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%) randomized to chemotherapy received trametinib.
Of 322 patients enrolled, 54% were male, the median age was 54 years, all had baseline ECOG performance status of 0 or 1, and 64% had M1c disease. All patients had tumor tissue with mutations in BRAF V600E (87%), V600K (12%), or both (<1%) on centralized testing.
A statistically significant prolongation of investigator-assessed PFS was demonstrated for patients randomized to the trametinib arm compared to those receiving chemotherapy [HR 0.47 (95% CI: 0.34, 0.65); p < 0.0001, log-rank test]. The median PFS was 4.8 and 1.5 months in the trametinib and chemotherapy arms, respectively. The PFS analysis assessed by blinded independent central review was consistent with the investigator results.
The investigator-assessed, objective response rates were 22% (95% CI: 17, 28) for the trametinib arm and 8% (95% CI: 4, 15) for the chemotherapy arm. The analysis of overall survival was not mature.
There was no evidence of anti-tumor activity with trametinib in patients who had received prior BRAF inhibitor therapy. This was evaluated in a single-arm, multicenter, international trial enrolling 40 patients with BRAF V600E 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.
The most frequent (≥ 20% incidence) adverse reactions from trametinib were rash, diarrhea and lymphedema.
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.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm
, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).