New systemic therapies for metastatic melanoma - mapk inhibitors and

Metastatic melanoma has a poor prognosis and until recently systemic therapy was ineffective. Advances in the understanding of tumour biology and immune regulation have led to the development of targeted agents that have changed clinical practice. BRAF and MEK inhibitors target the constitutively active MAPK growth-signalling pathway in BRAF-mutant melanoma. They have a rapid mode of action, cause tumour regression in most patients, and offer improved survival compared with conventional chemotherapy. However, the near-universal and quite rapid development of acquired resistance is a major concern. Drugs targeting T cell regulation also show promise, with the anti-CTLA-4 antibody ipilimumab demonstrating a durable clinical benefit in a minority of patients but an overall survival advantage over conventional chemotherapy, while the emerging anti-PD-1 and anti-PD-L1 antibodies look likely to improve response rates with less toxicity. Trials of combinations of these therapies and new drugs targeting other molecular aberrations are under way, as are efforts to understand the mechanisms behind drug resistance. Melanoma is increasing in incidence, and while it is curable in the majority of early stage cases, visceral metastatic disease carries an extremely poor prognosis. Until recently, systemic treatments were largely ineffective, with response rates of less than 10% and median overall survival times of only six to nine months. 1 The last few years have witnessed a revolution in systemic treatment, founded upon a rapidly evolving understanding of tumour biology and immune physiology, providing significant improvements in outcomes for patients with metastatic melanoma. Central to this process has been the discovery of specific driver oncogenes that exist in a large proportion of melanoma patients, as well as an improved understanding of the processes involved in immune regulation. Several targeted drugs have recently been shown to be more effective than previous systemic regimens, but while these have rapidly entered routine clinical practice, a large number of trials are under way, designed to build on the early success of these therapies.