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Dabrafenib–trametinib combination extended survival in metastatic melanoma
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The combination of dabrafenib and trametinib significantly extended OS compared with vemurafenib monotherapy in patients with treatment-naive metastatic melanoma who harbored BRAF V600E or V600K mutations, according to results of a randomized, open-label phase 3 study.
The regimens demonstrated comparable toxicity profiles, researchers wrote.
Caroline Robert
“Together with the previously reported phase 2 and 3 trials of dabrafenib plus trametinib as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,” Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave-Roussy in Paris, and colleagues wrote.
The analysis included 704 patients with BRAF V600 mutations. Robert and colleagues randomly assigned half of the patients to first-line therapy with 150 mg twice-daily dabrafenib (Tafinlar, GlaxoSmithKline) plus 2 mg once-daily trametinib (Mekinist, GlaxoSmithKline). The other patients received 960 mg twice-daily oral vemurafenib (Zelboraf; Genentech, Daiichi Sankyo).
OS served as the primary outcome. Secondary outcomes included PFS, overall response rate, duration of response and safety.
Results of a preplanned interim analysis showed a higher rate of OS at 1 year in the combination arm (72% vs. 65%), translating to an HR for death in the combination group of 0.69 (95% CI, 0.53-0.89).
The study was halted for efficacy after the prespecified interim stopping boundary was crossed, according to the researchers. At that time, patients initially assigned vemurafenib were able to cross over to the combination regimen.
Patients assigned the dabrafenib–trametinib combination also demonstrated longer median PFS (11.4 months vs. 7.3 months; HR=0.56; 95% CI, 0.46-0.69), a higher rate of objective response (64% vs. 51%; P<.001) and a longer median duration of response (13.8 months vs. 7.5 months).
Thirteen percent of patients in the combination arm achieved complete response compared with 8% of patients in the monotherapy arm.
Researchers reported similar rates of severe adverse events and study-drug discontinuations in both treatment arms. Incidence of cutaneous squamous cell carcinoma and keratoacanthoma was higher in the vemurafenib arm (18% vs. 1%).
Disclosure: The study was funded by GlaxoSmithKline.
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