The combination of dabrafenib and trametinib is safe and effective in BRAF-mutant melanoma.
Major finding: The combination of dabrafenib and trametinib is safe and effective in BRAF-mutant melanoma.
Clinical Relevance:: Secondary skin cancers were less common after combination therapy than with monotherapy.
Impact: MEK inhibitors can delay the emergence of acquired resistance to BRAF inhibition.
Blockade of MAPK signaling through targeted inhibition of BRAF or its downstream effector MEK has been associated with improved progression-free and overall survival in patients with metastatic melanomas harboring activating BRAF V600 mutations. However, patients commonly experience disease progression due to MAPK reactivation or other resistance mechanisms, and some patients treated with BRAF inhibitors develop secondary keratoacanthomas or cutaneous squamous cell carcinomas due to paradoxical MAPK pathway activation. Flaherty and colleagues tested whether combined use of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) would circumvent MAPK reactivation and prevent the development of acquired resistance and secondary skin cancers in patients with BRAF-mutant melanoma. The safety and pharmacokinetic activity of combination dabrafenib and trametinib therapy were evaluated in a phase I dose-escalation trial of 85 patients. There were no adverse drug interactions, and the maximum tolerated dose combination was not reached. In an open-label phase II trial, 162 patients were randomized to receive either dabrafenib plus trametinib or dabrafenib monotherapy. Strikingly, the progression-free survival was 9.4 months in the combination group compared with 5.8 months in the dabrafenib monotherapy group, and 76% of patients on combination therapy had a complete or partial response whereas only 54% of patients on dabrafenib monotherapy responded. Furthermore, the incidence of cutaneous squamous cell carcinomas was 19% in the dabrafenib monotherapy group compared with only 7% in the combination group. Patients treated with dabrafenib and trametinib experienced more frequent fevers, chills, nausea, and vomiting than patients on dabrafenib monotherapy, but these adverse effects were manageable. Together, these findings show that combined use of BRAF and MEK inhibitors is safe and may improve clinical outcome in patients with BRAF-mutant metastatic melanoma.
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012 Sept 29 [Epub ahead of print].
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