Dabrafenib and Trametinib Combination Granted Priority Review Designation by FDA

The FDA has granted Priority Review designation to dabrafenib (Tafinlar) and trametinib (Mekinist) as a combination treatment for patients with unresectable or metastatic melanoma with a BRAF^V600E/K mutation.

According to a statement from the drugs’ manufacturer, GlaxoSmithKline, the FDA has set target dates in early January 2014 to review the trametinib and dabrafenib supplements. The drugs were approved simultaneously as single-agents earlier this year.

Each drug treats melanoma through a different mechanism of action. Dabrafenib is a BRAF inhibitor approved to treat patients who express the BRAF^V600E mutation, while trametinib, a MEK 1/2 inhibitor is approved to treat patients with either the BRAF^V600E or BRAF^V600K mutation. Both drugs act on the RAS kinase pathway, dabrafenib at an earlier point than trametinib. A patient will typically develop resistance to dabrafenib monotherapy after about 5 to 7 months. The addition of trametinib helps overcome the tumor’s resistance mechanism, allowing for a more durable response to treatment

The Priority Review was granted based on the results of a randomized phase I/II study that compared combination therapy with dabrafenib and trametinib to dabrafenib monotherapy in adult patients with BRAF^V600E/K mutation-positive metastatic melanoma.

According to the study that was published in the New England Journal of Medicine, progression-free survival (PFS), response rate, and duration of response favored the combination of dabrafenib and trametinib compared to single-agent dabrafenib for patients with BRAF^V600E/K —positive metastatic melanoma.

The phase II study randomized 162 patients with BRAF^V600E/K —positive metastatic melanoma to one of three treatment arms: monotherapy with dabrafenib at 150 mg/BID; combination of dabrafenib at 150 mg/BID plus 1 mg of once-daily trametinib; or concurrent full doses of both drugs (dabrafenib at 150 mg/BID; once-daily trametinib at 2 mg). The median PFS for patients who received the full dose combination was 9.4 months, as compared with 5.8 months with dabrafenib monotherapy (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001).

Side effects associated with MEK inhibitors, including peripheral edema, hypertension, decreased cardiac ejection fraction, and ocular events had a higher occurrence in the combination therapy while side effects associated with BRAF inhibitors of hyperproliferative skin lesions occurred less frequently in the combination group when compared to the monotherapy group. 

In February 2013, the global phase III COMBI-AD study began, aiming to analyze the combination of dabrafenib and trametinib as adjuvant therapy for patients with melanoma.

The study will evaluate whether the combination of agents can delay or prevent the recurrence of melanoma (Relapse Free Survival) in patients with Stage IIIa, IIIb, or IIIc BRAF^V600E/K mutation-positive melanoma that has been completely removed by surgery. The study will also evaluate the safety profile of the dabrafenib-trametinib combination in this treatment setting.

"The patients included in this trial are at high risk of their melanoma returning after surgery and there are currently few treatment options to reduce this risk,” Rafael Amado, MD, Head of Oncology R&D for GlaxoSmithKline said in a statement when the trial was announced. "Given the efficacy and safety findings observed with combined dabrafenib-trametinib treatment in the metastatic setting, we are investigating whether the combination administered after surgery can help these patients live longer without melanoma recurrence.”

There are two additional phase III studies ongoing, aimed to evaluate the combination of dabrafenib and trametinib for patients with metastatic BRAF^V600 melanoma.

Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med 2012; 367:1694-1703November 1, 2012DOI: 10.1056/NEJMoa1210093