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The role of MEK inhibitors in the treatment of metastatic melanoma

Grimaldi, Antonio M.; Simeone, Ester; Ascierto, Paolo A.

doi: 10.1097/CCO.0000000000000050

Purpose of review BRAF and NRAS mutations can exert an oncogenic effect and are a target for novel therapeutic strategies. Selective MEK inhibitors inhibit growth and induce cell death in BRAF and NRAS mutated melanoma cell lines. The first MEK inhibitor (trametinib) has recently been approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors and several more are in clinical development.

Recent findings MEK inhibition is associated with improved response rate, progression-free survival, and overall survival in patients with BRAF-mutated metastatic melanoma. Less clinical benefit has been observed in patients previously treated with a BRAF inhibitor compared with BRAF-inhibitor-naïve patients. Data also suggest clinical activity in patients with NRAS-mutated melanoma. Combination therapy with a BRAF inhibitor may improve the efficacy and reduce BRAF-inhibition-associated side effects.

Summary MEK inhibitors represent a new treatment option in BRAF and NRAS mutated melanoma. As monotherapy, MEK inhibitors appear to provide minimal benefit in patients previously treated with a BRAF inhibitor, so they should be reserved for BRAF-inhibitor-naïve patients. Combined BRAF and MEK inhibition seems to provide a greater benefit than BRAF inhibitor monotherapy. MEK inhibition has also shown efficacy in NRAS-mutated patients, for whom there is no specific targeted therapy.

Istituto Nazionale Tunori Fondazione ‘G. Pascale’, Naples, Italy

Correspondence to Paolo A. Ascierto, MD, Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori Fondazione ‘G. Pascale’, Via Mariano Semmola, 80131 Naples, Italy. Tel: +39 81 5903 236; fax: +39 81 5903 841; e-mail:,

© 2014 Lippincott Williams & Wilkins, Inc.