Challenges in the Delivery of Therapies to Melanoma Brain Metastases

Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. Recent approval of several molecularly targeted agents and biologics has brought hope to patients with this previously untreatable disease. However, patients with symptomatic melanoma brain metastases have often been excluded from pivotal clinical trials. This may be in part attributed to the fact that several of the approved small-molecule molecularly targeted agents are substrates for active efflux at the blood–brain barrier, limiting their effective delivery to brain metastases. We believe that successful treatment of melanoma brain metastases will depend on the ability of these agents to traverse the blood–brain barrier and reach micrometastases that are often not clinically detectable. Moreover, overcoming the emergence of a unique pattern of resistance, possibly through adequate delivery of combination targeted therapies in brain metastases, will be important in achieving a durable response. These concepts, and the current challenges in the delivery of new treatments to melanoma brain metastases, are discussed in this review.