Time for a New Paradigm in the Treatment of Metastatic Melanoma

Abstract

Metastatic melanoma is a very common disease with an increasing incidence worldwide and is notoriously difficult to treat. The long-established treatments including dacarbazine and interleukin-2 have shown limited response rates and are associated with significant toxicities. More recently, treatments have been developed that decrease inhibition of T-cell action against melanomas. Among these, ipilimumab was recently approved for use in metastatic melanoma and has shown improved overall survival (OS) and progression-free survival rates (PFS). Another such treatment currently in development is the monoclonal antibody, anti-PD-1. This blocks PD-1 inhibition of T-cells and has shown promising response rates in early clinical trials. Another treatment approach is to use targeted therapies in patients with mutations in BRAF or CKIT signaling pathways and it is vital that the mutational status of these genes be determined in patients with metastatic melanoma to best determine effective therapeutic options. Vemurafenib was recently approved for metastatic melanoma and targets the BRAF V600E mutation which occurrs in about 50 % of cutaneous melanomas. Recent results from the ongoing Phase III BRIM-3 study comparing vemurafenib with dacarbazine showed that median 12-month OS rates and the risk of death were reduced with vemurafenib. Other BRAF inhibitors such as dabrafenib and MEK inhibitors such as trametinib are also in development. New treatments in ongoing clinical trials coupled with an improved biologic understanding are likely to improve responses and outcomes for patients with metastatic melanoma.