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U.S. Department of Health and Human Services

Drugs

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Trametinib and Dabrafenib

The U. S. Food and Drug Administration granted accelerated approval to trametinib (Mekinist tablets, GlaxoSmithKline, LLC) and dabrafenib (Tafinlar capsules, GlaxoSmithKline, LLC) for use in combination in the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test.

Trametinib was previously approved in 2013 as a single agent for treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.   Dabrafenib was also approved in 2013 as a single agent for treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway.
 
Approval of the combination therapy was based on the demonstration of durable objective responses in a multicenter, open-label, randomized (1:1:1), active-controlled, dose-ranging trial enrolling 162 patients with histologically confirmed Stage IIIC or IV melanoma determined to be BRAF V600E or V600K. No more than one prior chemotherapy regimen and/or interleukin-2 were permitted. Patients with prior exposure to BRAF inhibitors or MEK inhibitors were ineligible.
 
Patients were randomized to receive trametinib 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily (n=54), trametinib 1 mg orally once daily in combination with dabrafenib 150 mg orally twice daily (n=54), or single-agent dabrafenib 150 mg orally twice daily (n=54). Of the 162 patients enrolled, 57% were male, the median age was 53 years, all had baseline ECOG PS of 0 or 1, 67% had M1c disease, and 81% had not received prior anticancer therapy for unresectable or metastatic disease. All patients had tumor tissue with mutations in BRAF V600E (85%) or V600K (15%) on local or centralized testing.
 
The investigator-assessed objective response rates and response duration were 76% (95% CI: 62, 87) and 10.5 months (95% CI: 7, 15), respectively, in the trametinib 2 mg plus dabrafenib combination arm and 54% (95% CI: 40, 67) and 5.6 months (95% CI: 5, 7), respectively, in the single-agent dabrafenib arm. Objective response rates were similar in subgroups defined by BRAF V600 mutation subtype, V600E and V600K. Analyses of objective response rates based on blinded independent central review were consistent with the investigator results.
 
The incidence of cutaneous squamous cell carcinoma (including squamous cell carcinomas of the skin and keratoacanthomas), the trial’s primary safety endpoint, was 7% (95% CI: 2, 18) in the trametinib 2 mg plus dabrafenib combination arm compared to 19% (95% CI: 9, 32) in the single-agent dabrafenib arm.
 
The most frequent (greater than or equal to 20% incidence) adverse reactions from trametinib in combination with dabrafenib were pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. The most frequent grades 3 and 4 adverse events (greater than or equal to 5% incidence) were acute renal failure, pyrexia, hemorrhage, and back pain.
 
Serious adverse drug reactions occurring in patients taking trametinib in combination with dabrafenib were hemorrhage, venous thromboembolism, new primary malignancy, serious febrile reactions, cardiomyopathy, serious skin toxicity, and eye disorders such as retinal pigmented epithelial detachments.
 
Granting of this accelerated approval is contingent upon the successful completion of the ongoing MEK115306 trial to verify the clinical benefit of trametinib for use in combination with dabrafenib. MEK115306 is an international, multicenter, randomized (1:1), double-blind, placebo-controlled trial comparing the combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy in approximately 340 patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E or V600K mutation-positive cutaneous melanoma.  The primary endpoint is progression-free survival.  Overall survival is a key secondary endpoint.
 
The recommended dose and schedule for trametinib and dabrafenib when used in combination is trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily continued until disease progression or unacceptable toxicity occurs. Trametinib and dabrafenib should be taken at least one hour before or two hours after a meal. The once daily dose of trametinib can be taken at the same time as either dose of dabrafenib.
 
Full prescribing information is available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204114s001lbl.pdf
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202806s002lbl.pdf
 
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).