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Dabrafenib/Tametinib Improves Survival in Phase III Melanoma Study
Overall survival (OS) results from the phase III COMBI-d trial have demonstrated a statistically significant reduction in the risk of death (hazard ratio [HR], 0.71; P = 0.011) for the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), both marketed by GlaxoSmithKline, compared with dabrafenib monotherapy in patients with BRAF V600E/K mutation-positive metastatic melanoma.
The completion of this study was a post-marketing requirement for the FDA’s accelerated approval of the combination treatment. Final data will be submitted to regulatory authorities for review in the coming months.
The pivotal, randomized, double-blind COMBI-d trial compared the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib with single-agent therapy with dabrafenib and placebo in 423 patients with unresectable (stage IIIC) or metastatic (stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study’s primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included OS, the objective response rate, the duration of response, and safety. There was no crossover between treatment arms.
Previous analyses from the August 2013 data cut for the COMBI-d study showed that treatment with the dabrafenib/tametinib resulted in a 25% reduction in the risk of disease progression and/or death compared with dabrafenib alone (HR, 0.75; P = 0.035). The median PFS was 9.3 months in patients treated with the combination compared with 8.8 months in patients treated with dabrafenib alone.
At the time of the primary analysis, the most common adverse events (AEs) in the combination-treatment arm included pyrexia, fatigue, headache, nausea, chills, athralgia, diarrhea, rash, hypertension, and vomiting. More patients had AEs leading to dose modifications with combination treatment compared with dabrafenib monotherapy. An increased incidence (51% vs. 28%) and severity (grade 3, 6% vs. 2%) of pyrexia occurred with the combination. An increased incidence of hyperkeratosis (32% vs. 3%) occurred with dabrafenib monotherapy.
The FDA has approved the combination use of trametinib and dabrafenib in patients with unresectable or metastatic melanoma who have the BRAF V600E/K mutation.
Source: GSK; February 6, 2014.