Trametinib Shows Activity in Previously Treated but BRAF Inhibitor–naive BRAF-mutant Melanoma


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In a multicenter phase II study, trametinib showed “significant clinical activity” in a cohort of BRAF inhibitor–naive patients with BRAF-mutant cutaneous melanoma previously treated with chemotherapy and/or immunotherapy. Only minimal clinical activity, however, was observed among a cohort of patients who had previously been treated with a BRAF inhibitor. Results were published in the Journal of Clinical Oncology.

All patients in the trial received 2 mg of the MEK1/MEK2 inhibitor trametinib orally once daily. The median time for receiving the study drug was 56 days for those previously treated with a BRAF inhibitor (dabrafenib or vemurafenib [Zelboraf]) and 120 days for those previously treated with chemotherapy and/or immunotherapy.

Among the 40 patients who had previously been treated with a BRAF inhibitor, none had confirmed objective responses and 11 (28%) had stable disease. The median progression-free survival was 1.8 months. The researchers concluded that these data suggest that “BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy.”

Among the 57 patients who had not previously been treated with a BRAF inhibitor, the confirmed response rate was 25%. One patient (2%) had a complete response, and 13 patients (23%) had partial responses. In addition, 29 patients (51%) had stable disease. The median progression-free survival was 4.0 months.

“Activity was broad,” the researchers noted, with objective responses observed in patients with BRAF V600E and V600K (the more common BRAF mutations), as well as rare BRAF mutations. “These data support further evaluation of trametinib in BRAF inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma,” the investigators stated. They also noted that trametinib monotherapy could be useful for patients who cannot tolerate a BRAF inhibitor.

“The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed,” the researchers reported. No treatment-related deaths occurred, and only one grade 4 adverse event, which was pulmonary embolism. ■

Kim KB, et al: J Clin Oncol 31:482-489, 2013



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