The role of systemic therapies in the management of melanoma brain metastasesLyle, Megana,b; Long, Georgina V.a,bCurrent Opinion in Oncology: March 2014 - Volume 26 - Issue 2 - p 222–229 doi: 10.1097/CCO.0000000000000057 MELANOMA AND OTHER SKIN NEOPLASMS: Edited by Reinhard Dummer Abstract Author Information Purpose of review: Brain metastases in metastatic melanoma are highly prevalent and are associated with significant morbidity and a poor prognosis. Local therapy (surgery or radiotherapy) has been the mainstay of treatment, due in part to the lack of efficacy of systemic therapy. This review will focus on new systemic therapies for metastatic melanoma and their evolving role in the management of brain metastases. Recent findings: BRAF inhibitors have demonstrated efficacy in active (i.e. untreated or progressing) brain metastases in BRAFV600 mutated metastatic melanoma. The cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, has also shown activity, particularly in asymptomatic metastases. Studies of programmed death 1/programmed death ligand 1 checkpoint inhibitors and combination BRAF and MEK inhibitor therapy in brain metastases are planned. Emerging evidence on the molecular biology of melanoma brain metastases, particularly the role of the phosphatidylinositol 3-kinase-AKT pathway, may identify additional therapeutic targets. Summary: The development of systemic therapy effective in controlling both intra-cranial and extra-cranial melanoma metastases has resulted in a change in the paradigm of management. More research is required in patients with active brain metastases to improve patient outcomes, including studies early in the development of novel therapies, and studies to determine the safe and effective combination or sequencing of local and systemic therapies. aMelanoma Institute Australia bThe University of Sydney, Sydney, Australia Correspondence to Dr Georgina V. Long, MB, BS, PhD, FRACP, Melanoma Institute Australia and The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2060, Australia. Tel: +61 2 9911 7200; e-mail: firstname.lastname@example.org © 2014 Lippincott Williams & Wilkins, Inc.