Systemic therapies for melanoma brain metastases: which drug for whom and when?

Melanoma brain metastases are common, difficult to treat, and are associated with a poor prognosis. Historically, due to the poor activity of chemotherapeutic agents in melanoma, the management of brain metastases was centred on local treatments such as surgery, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) depending on the clinical presentation. New systemic therapies have now evolved; kinase inhibitors targeting BRAF mutated melanoma cells and activating checkpoint inhibitors that activate an immune anti-tumour response, resulting in significantly improved survival and quality of life for patients with metastatic melanoma and these drugs have demonstrated activity in melanoma brain metastases. As the landscape shifts to incorporate these new systemic agents with the available local therapies, further research into using appropriate combinations or sequences of various treatments, especially for active or progressing melanoma brain metastasis, is required. This review will examine the evidence for systemic therapies in patients with active melanoma brain metastasis (untreated or treated and progressed) and highlight active and evolving clinical trials in this challenging field.