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

Purpose: 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 BRAF-mutant melanoma.

Patients and methods: This 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.

Results: In cohort A (n = 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 = 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.

Conclusion: Trametinib 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-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

Trial registration: ClinicalTrials.gov NCT01037127.

Fig 1.

Trial design.

Fig 2.

Best percentage change from baseline in target lesions for (A) cohort A (radiographic scan data was incomplete or unavailable for 5 patients) and (B) cohort B (radiographic scan data was incomplete or unavailable for two patients). Staging was according to the American Joint Committee on Cancer (AJCC) system. (*) Patients with prior brain metastases; (†) patients who discontinued prior BRAF inhibitor because of toxicity; (K) patients with the V600K mutation.

Fig 3.

Kaplan-Meier estimated survival for all patients by cohort: (A) progression-free survival (PFS) for cohort A, (B) PFS for cohort B, (C) overall survival (OS) for cohort A, and (D) OS for cohort B. The bars represent the date of the last adequate tumor assessment before the data cutoff among patients with censored data without disease progression or death.

Fig A1.

Pharmacokinetic analysis. (A) Individual plasma trametinib concentration versus actual time postdose observed on day 15. (B) Individual plasma predose trametinib concentration observed at weeks 4, 8, and 12.