Systemic Therapies for Melanoma Brain Metastases: Which Drug for Whom and When?

Sangeetha Ramanujam; Dirk Schadendorf; Georgina V. Long


Chin Clin Oncol. 2015;4(2) 

In This Article

Abstract and Introduction


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.


Metastatic melanoma (stage IIIc unresectable or stage IV) is associated with a poor prognosis, and until recently, a median overall survival (OS) of 6–9 months.[1] For patients who develop brain metastasis, the median survival is reduced to 17 to 22 weeks.[2,3] The incidence of overt brain metastasis at first presentation is approximately 20% and approximately 50% of stage IV melanoma patients develop brain metastases during the course of their disease.[3] The presence of BRAF or NRAS mutations increases the risk of developing brain metastasis at first diagnosis of metastatic disease.[4] In addition to reduced life expectancy, patients with symptomatic lesions experience neurocognitive decline and poor quality of life.[5] The aim of treatment is to reduce neurological symptoms, minimise cognitive decline and improve survival. Recently, incorporation of such patients into clinical trials assessing newer systemic therapies has provided increased therapeutic options, and raises questions regarding the optimal selection and combinations of treatment modalities for brain metastasis.