Trametinib (Mekinist®) in combination with dabrafenib (Tafinlar®) for treatment of unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations that are detected by an FDA-approved test.
Approval based on results from a phase 1/2 study designed to assess the combination of dabrafenib and trametinib at the recommended dose of 150 mg/2 mg versus a 150-mg dose of dabrafenib alone.
Data from the randomized phase 2 component of the phase 1/2 open-label study demonstrated an overall response rate of 76% in the combination treatment arm versus 54% in the dabrafenib-alone arm.
Results also revealed a median duration of response of 10.5 months in the combination treatment arm versus 5.6 months in the dabrafenib-alone arm.
Combining a BRAF inhibitor with a MEK inhibitior results in a significant delay in the emergence of resistance, longer median progression free survival than with dabfrafenib alone, and decrease in BRAF inhibitior induced skin tumors.
COMBI-AD study of patients with Stage III completely resected melanoma with BRAF mutation were assigned to dabrafenib and trametinib or placebo: estimated 3 year relapse free survival was 58% with dabrafenib and trametinib vs. 39% for placebo, decreasing the risk for death or recurrence by 53%.
In the above study patients underwent complete surgical resection of stage IIIA, IIIB, IIIC BRAF V 600E or 600K mutant melanoma.
The most frequently occurring adverse reactions are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, edema peripheral, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.
The main side effect is pyrexia occurring in 63% of patients.
Combination treatment with trametinib and dabrafenib is associated with serious side effects, including: new primary cutaneous malignancies, tumor promotion in wild-type BRAF melanoma, hemorrhagic events, venous thromboembolic events, cardiomyopathy, ocular toxicities, interstitial lung disease, febrile drug reactions, serious skin toxicity, hyperglycemia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency and embryofetal toxicity.
Among pediatric patients with low-grade glioma with BRAFV 600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression free survival and there is safety profile in standard chemotherapy is first-line therapy.
Cutaneous squamous cell carcinoma, including keratocanthoma occurred in 7% patients receiving a combination of the above drugs.
Dermatologic evaluation prior to initiation of the above combination of drugs should be done every two months while on therapy and for up to six months following discontinuation.