title: Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond.
abstract: 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, with further improvements expected with new compounds and combinations. The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab). These drugs proved vastly superior to conventional chemotherapy, however response, resistance and toxicity were limitations. The second major advance is the development of other immune checkpoint blocking agents, including PD-1 and PD-L1 antibodies, and the use of BRAF and MEK inhibitors in combination, with a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes for patients with melanoma further, trials are underway examining the combination of MAPK inhibitors, immunotherapies and other pathway inhibitors and adjuvant studies of many of these agents have commenced.
authors.affiliation: Melanoma Institute Australia, Sydney, Australia; The University of Sydney, Sydney, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; CTLA4; Immunotherapy; Inhibitor; KIT; Melanoma; NRAS; PD-1; PD-L1; Targeted therapy