New therapeutic options in systemic treatment of advanced cutaneous melanoma

For many years systemic treatment of advanced/metastatic melanoma has been based on chemotherapy or immunotherapy. However, even very toxic regimens (e.g., polychemotherapy, bio-chemotherapy or immunotherapy with HD-IL-2) despite increased response rates as compared with standard dacarbazine monotherapy have not improved patients' outcomes. Over the last two decades, a huge effort, made in order to determine the molecular and immunological mechanisms responsible for biology of melanoma led to development of novel targeted agents.

The aim of this article is to summarize data on novel targeted agents used for treatment of metastatic melanoma. The authors searched PubMed, EMBASE and abstracts from ASCO, ESMO, AACR congresses for Phase II/III clinical studies evaluating novel immunomodulating agents and kinase inhibitors in melanoma patients.

Elucidation of the crucial role of MAPK pathway and BRAF kinase mutations in particular has led to development of specific small molecule kinase inhibitors (vemurafenib, dabrafenib, trametinib), and new insight into molecular mechanisms responsible for immune response and tolerance resulted in development of immunomodulatory agents (ipilimumab, anti-PD1, anti-PD-L1). The introduction of novel drugs has changed the natural history of melanoma. However, it has also generated new clinical challenges that have to be resolved as soon as possible.