Advances in the systemic treatment of melanoma brain metastases

Of the solid tumor types that metastasize to the brain, melanoma has the highest propensity to form brain metastases. In addition, much remains unknown regarding the pathophysiology involved in melanoma cell extravasation through the blood- brain barrier, which enables interactions with the microenvironment, and melanoma cell transcriptomic responses to brainspecific cues. However, recent developments in targeted therapy and immunotherapy have generated considerable optimism regarding the treatment of metastatic melanoma. Although robust efficacy data exist on systemic therapy treatment of extracranial melanoma, data in the setting of melanoma brain metastases (MBM) are limited, primarily because patients with MBM are typically excluded from clinical trials. However, several clinical trials focusing on patients with MBM are now complete, and more are underway. Clinical evaluation of serine/threonine-protein kinase B-Raf inhibition in combination with MEK inhibition for MBM produced intracranial response rates of close to 60%, suggesting that inhibition of the mitogen-activated protein kinase pathway has the potential to further improve MBM outcomes. For immunotherapy, there is now increasing evidence that checkpoint inhibitors may also be effective in MBM with a high rate of durable intracranial responses observed with combination therapy. Furthermore, radiotherapy-particularly MBM treatment with mainstay stereotactic radiosurgery- appears to be safe and effective when combined with systemic therapy. Finally, evolving magnetic resonance imaging capabilities have inspired new approaches to the measurement of tumor burden and treatment responses. This review evaluates current published evidence describing MBM as a multifaceted disease and presents an overview of currently available and investigational treatments for patients with MBM.