MEK162 is well tolerated and shows activity in patients with BRAF- and NRAS-mutant melanoma.

  • Major finding: MEK162 is well tolerated and shows activity in patients with BRAF- and NRAS-mutant melanoma.

  • Approach: The safety and efficacy of MEK162 were evaluated in an open-label, nonrandomized phase II trial.

  • Impact: MEK162 may benefit patients with NRAS-mutant melanoma and those with brain metastases.

The mitogen-activated protein kinase (MAPK) pathway is frequently activated in melanoma via mutations in the BRAF and NRAS oncogenes and can be targeted using selective BRAF inhibitors such as vemurafenib in BRAF-mutant tumors. Inhibitors of MAP/ERK kinase (MEK) have also shown clinical benefit alone and in combination with vemurafenib in BRAF-mutant tumors. However, it is not clear whether MEK inhibitors are effective in patients with BRAF wild-type, NRAS-mutant melanoma, which is associated with poor prognosis. Ascierto and colleagues investigated the efficacy and safety of MEK162, a small-molecule non–ATP-competitive, allosteric MEK1/2 inhibitor in an open-label, nonrandomized phase II trial in patients with advanced melanoma. Thirty patients with NRAS mutations and 41 patients with BRAF mutations, most of whom had been previously treated with chemotherapy, immunotherapy, or a BRAF inhibitor but not a MEK inhibitor, received at least one dose of MEK162, and the proportion of patients with an objective response was assessed as the primary endpoint. Although no patients had a complete response, 6 patients (20%) in the NRAS-mutant group and 8 patients (20%) in the BRAF-mutant group had a partial response. In addition, 19 patients (63%) with NRAS mutations and 21 patients (51%) with BRAF mutations achieved stable disease. Intriguingly, MEK162 treatment also reduced the size of brain metastases in 2 patients with NRAS-mutant tumors. However, no responses to MEK162 treatment were reported in patients previously treated with a BRAF inhibitor. MEK162 was well tolerated, and toxicities were manageable; 4 patients experienced serious adverse events, and the most common toxicities included peripheral edema, elevated creatine phosphokinase levels, and skin- and gastrointestinal-related events. These findings support additional clinical testing of MEK162 in metastatic melanoma and suggest that this drug may benefit patients with NRAS-mutant tumors.

Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013 Feb 13 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013