Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor

Abstract

A B S T R A C TPurpose BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAFmutant melanoma. Patients and MethodsThis was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. ResultsIn cohort A (n ϭ 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n ϭ 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. 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. ConclusionTrametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitornaive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

NCCN Guidelines Insights: Melanoma, Version 3.2016

“…37,38,40 Moreover, in an open-label phase II study, trametinib failed to induce objective responses in 40 patients previously treated with a BRAF inhibitor. 41 Although MEK inhibitor monotherapy has limited utility for treating advanced metastatic melanoma, phase III trials have now demonstrated that combination therapy with a BRAF and MEK inhibitor has better efficacy than BRAF inhibitor monotherapy for previously untreated unresectable or metastatic disease (Table 8).…”

MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

“…Two cases of central serous retinopathy and no cases of retinal vein occlusion were reported in the phase II trial. 16 A phase III trial randomized 322 patients with BRAF mutant melanoma to treatment with GSK1120212 vs standard chemotherapy. They found that the progression-free survival was 4.8 months in the MEK inhibitor group vs 1.5 months in the standard chemotherapy group.…”

Intratumoral Molecular Heterogeneity in a BRAF-Mutant, BRAF Inhibitor-Resistant Melanoma: A Case Illustrating the Challenges for Personalized Medicine

“…His subsequent systemic therapies included singleagent trametinib (previously GSK1120212, an MEK inhibitor; ref. 8), the combination of dabrafenib (previously GSK2118436, a BRAF inhibitor) and trametinib (9) and E7080 (a multikinase inhibitor with specific activity against VEGF), and finally he was rechallenged with vemurafenib ( Fig. 1A).…”