Mekinist and Tafinlar Approved for Advanced Melanoma with BRAF Mutations

June 2013, Vol 4, No 5 - FDA Approvals, News & Updates


On the same day, the FDA approved 2 targeted oral therapies for patients with melanoma. The 2 therapies were both developed by Glaxo­SmithKline and are targeting similar, but not the same, populations of patients with melanoma and a BRAF mutation. Both drugs were approved concurrently with the FDA approval of a companion diagnostic assay THxID BRAF (manufactured by bioMérieux) for the detection of BRAF V600E and BRAF V600K mutations.

Trametinib (Mekinist tablet) was approved for the treatment of patients with metastatic or unresectable melanoma and the BRAF V600E and BRAF V600K mutation who have not been previously treated with a BRAF  inhibitor therapy. The recommended dosage for trametinib is 2 mg orally until disease progression or unacceptable toxicity, to be taken ≥1 hour before or 2 hours after a meal.

The FDA’s approval of trametinib was based on a demonstrated improvement in progression-free survival (PFS) in a multicenter, international, open-label, active-controlled trial with 322 patients with stage IIIc or stage IV melanoma with either BRAF V600E and BRAF V600K mutation. Patients with >1 previous chemotherapy regimen or those who received BRAF or MEK inhibitors were excluded from the trial.

The patients were randomized in a 2:1 ratio to oral trametinib 2 mg daily or to intravenous chemotherapy with dacarbazine or paclitaxel every 3 weeks. Overall, 51 (47%) patients in the chemotherapy arm received trametinib at the time of disease progression.

The median PFS was 4.8 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.34-0.65; P <.001).

Objective response rates were 22% with trametinib and 8% with chemotherapy. Data for OS were not mature.

In a single-arm trial of 40 patients with unresectable or metastatic melanoma and BRAF V600E or BRAF V600K mutation who had received previous BRAF inhibition therapy, the administration of trametinib showed no evidence of antitumor activity (ie, no response) in these patients.
The most common (≥20) adverse events (AEs) reported with trametinib were rash, diarrhea, and lymphedema. Serious AEs included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin reactions.

Dabrafenib (Tafinlar capsule) was approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation. Dabrafenib is not approved for patients with the wild-type melanoma (ie, without BRAF mutation); in those patients it could potentially lead to tumor promotion.

The recommended dosage is 150 mg twice daily until disease progression or until unacceptable toxicity.

Dabrafenib should be taken ≥1 hour before or 2 hours after a meal. The presence of BRAF V600E mutation must be confirmed before prescribing dabrafenib, which could potentially promote tumor growth in patients with wild-type melanoma.

The approval was based on a multicenter, international, open-label, randomized, active-controlled trial of 250 patients with treatment-naïve unresectable stage III or stage IV melanoma. A total of 28 patients in the dacarbazine arm received dabrafenib when their disease progressed.
The median PFS was 5.1 months with dabrafenib versus 2.7 months in the dacarbazine arm (HR, 0.33; 95% CI, 0.20-0.54; P <.001). The objective response rates were 52% with da­brafenib, which included 3% complete response, versus 17% with dacarbazine (P <.001). The median response duration was approximately 5 months in both arms. OS was not significantly different.

The most common (≥20%) AEs with dabrafenib included hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. Serious AEs involved new primary skin cancer, including cutaneous squamous-cell carcinoma, new primary melanoma, and keratoacanthomas; febrile drug reactions requiring hospitalization; hyperglycemia; and uveitis/iritis. Dabrafenib was approved with a medication guide informing patients of these serious risks. (May 29, 2013)