Trametinib, a MEK kinase inhibitor, is currently neither licensed in the Europe nor in the U.S. Its efficacy was tested in a phase III trial, comprising 322 patients with BRAF V600 mutation-positive melanoma. Patients were randomised in a 2:1 ratio to either trametinib or chemotherapy consisting of either dacarbazine or paclitaxel. Enrolled individuals could have received one prior line of therapy but the majority of patients that is about 70% were treatment-naïve.
Progression-free survival, the primary outcome was prolonged by 3.3 months for patients treated with trametinib in comparison to chemotherapy, yielding a hazard ratio of 0.45 (95%CI 0.33-0.63; p<0.001). Results for subgroups according to mutation-status and prior treatment, age, LDH levels, disease stage and sex mainly favoured the trametinib group. Only for older patients (≥65 years) and patients with V600K mutations statistical significance was not shown, but both groups comprised rather few patients. Median overall survival was not yet reached, but OS rates at 6 months were 81% vs 67%. Based on these results, crossing-over to the trametinib arm was given permission. The most common side-effects were rash, diarrhoea, fatigue and nausea, and more dose-interruptions (I 35% vs C 22%) and dose reductions (I 27% vs C 10%) due to AEs were observed in the trametinib group.
Treatment of melanoma has undergone substantial changes in the last years. Until recently, only few drugs with rather limited activity have been available, but now several new drugs can be used. Even though the activity of trametinib was shown in the phase III trial, best timing and sequencing of therapeutic options remain uncertain. Development of secondary resistance creates problems and further contributes to uncertainties on first-choice therapy. Moreover, duration of response and delay of resistance is believed to be overcome by combination therapies, for example trametinib and a BRAF inhibitor, potentially impacting considerably on treatment costs. As longs as direct head-to-head comparisons of new agents are missing, enrolment onto clinical trials might offer the best treatment strategy for patients with advanced/metastatic melanoma.