Richard Pazdur, MD
The FDA approved both dabrafenib (Tafinlar) and trametinib (Mekinist) for the treatment of patients with metastatic or unresectable melanoma, as well as a companion diagnostic to properly identify the patients exhibiting the mutations that are targeted by these agents.
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. Trametinib is a MEK inhibitor approved to treat patients with either the BRAF V600E
mutation. According to the FDA, approximately half of all cases of melanoma that arise in the skin exhibit a BRAF
While the drugs were approved at the same time, treat a similar group of patients, and have been studied in combination with one another, the approvals are for dabrafenib and trametinib as single agents and not as a combination treatment.
“Advancements in our understanding of the biological pathways of a disease have allowed for the development of Tafinlar and Mekinist, the third and fourth drugs the FDA has approved for treating metastatic melanoma in the past two years,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement, referring to the previous approvals of vemurafenib (Zelboraf) and ipilimumab (Yervoy) in 2011.
The approval of dabrafenib was based upon the results of the phase III BREAK-3 trial, which were published in the journal The Lancet
In that trial, 250 patients with a BRAF V600E
mutation were randomly assigned to receive either dabrafenib (n=187) or dacarbazine (n=63). According to the study’s results, the median progression-free survival (PFS) in the dabrafenib arm was 5.1 months compared with 2.7 months in the dacarbazine arm (hazard ratio [HR] = .30; 95% CI, 0.18–0.51; P
<.0001). At the data cutoff, 57% of patients receiving dabrafenib remained on treatment, compared with 22% in the dacarbazine arm. Adverse events that were grade 2 or higher were observed in 53% of patients receiving dabrafenib; the most common were skin-related toxic effects, fever, fatigue, arthralgia, and headache.
Trametinib was approved based on the results of the phase III METRIC trial, which were published in the New England Journal of Medicine
Patients with advanced melanoma with a BRAF V600E
mutation were randomized in a 2:1 ratio to receive either trametinib (n=214) or chemotherapy (n=108). The study found that the median PFS was 4.8 months in the trametinib arm compared with 1.5 months in the chemotherapy arm (HR= 0.45; 95% CI, 0.33 - 0.63; P
<0.001). The overall survival rate at six months was 81% in the trametinib arm compared with 67% in the chemotherapy arm despite crossover (HR = 0.54; 95% CI, 0.32 - 0.92; P
=0.01). Common adverse events included rash, diarrhea, and peripheral edema.
Alberto Gutierrez, PhD
The FDA also approved THxID BRAF test, a companion diagnostic used to identify patients exhibiting either the BRAF V600E
“The co-approval of Tafinlar and Mekinist and the second companion diagnostic for BRAF mutation detection demonstrates the commitment of pharmaceutical and diagnostic partners to develop products that detect and target the molecular drivers of cancer,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostic Devices and Radiological Health in the FDA’s Center for Devices and Radiological Health, in a statement.
According to the National Cancer Institute, an estimated 76,690 Americans are expected to be diagnosed with melanoma and 9,480 patients to die from the disease in 2013.
GlaxoSmithKline, based in Research Triangle Park, North Carolina, markets both drugs. The companion diagnostic is manufactured by bioMérieux of Grenoble, France.
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 July; 380(9839):358-65.
Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul;367(2):107-14.