The Role of Systemic Therapy in Melanoma Brain Metastases

A Narrative Review

Kainat Saleem; Diwakar Davar


Chin Clin Oncol. 2022;11(3):24 

In This Article

Abstract and Introduction


Background and Objective: Melanoma is a disease notorious for the development of brain metastases, with consequently poor outcomes for patients who develop melanoma brain metastases (MBM). The treatment options for patients with MBM were limited to radiotherapy and surgery. MBM patients, particularly those with symptomatic disease, were excluded from clinical trials of immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors. Recent post-approval studies have, demonstrated important roles for existing systemic ICIs and BRAF/MEK inhibitors in untreated MBM, dramatically altering the landscape of melanoma patients in general and MBM in particular. These trials have also identified key areas for which more effective strategies are needed including: symptomatic MBM, and leptomeningeal disease (LMD).

Methods: PubMed, Scopus and Embase databases were systematically queried to obtain records pertaining to the etiology of and treatment for MBM. Clinical trial databases were reviewed to obtain details regarding MBM clinical trials.

Key Content and Findings: We discuss the etiopathogenesis of MBM and the novel immune, molecular and metabolic features of MBM that make this disease a unique therapeutic challenge. We review advances in systemic therapy with ICIs and BRAF/MEK inhibitors in untreated MBM, along with novel combinations. Finally, we debate challenging situations such as LMD, and delineate novel treatments and new paradigms for therapeutic interventions.

Conclusions: The historically poor outcomes for MBM patients have been transformed with the advent of effective systemic therapies including ICIs and BRAF/MEK inhibitors. An improved understanding of the molecular and immunogenomic characterization of MBMs has provided new targets that are being exploited in the clinic.


Cutaneous melanoma exhibits the highest level of cerebral tropism of all cancer types, with up to 30–40% of advanced melanoma patients having melanoma brain metastases (MBM) at diagnosis,[1–3] and up to 75% at the time of death in autopsy series.[2] MBM are associated with a higher risk of complications and death compared to other cancers.[4,5] While surgical resection and stereotactic radiosurgery (SRS) are highly effective for local control of oligometastatic MBM,[2,6] patients with multiple brain metastases and/or leptomeningeal disease (LMD) are typically treated with whole-brain radiation therapy (WBRT) with poor outcomes. The prognosis of MBM patients has remained poor, with a median overall survival (OS) of 4–5 months, and a durable survival rate of 5%.[6]

Historically, patients with untreated brain metastases were excluded from clinical trials for all currently approved targeted and immune therapies given the uncertain penetrance of the blood-brain barrier (BBB) by systemic agents and consequent perceived uncertainties over central nervous system (CNS) efficacy. Several post-marketing clinical trials subsequently clarified that immune checkpoint inhibitors (ICI) and small molecules targeting BRAF and MEK kinases had intracranial activity in MBM patients. These trials also identified key areas for which more effective strategies are needed. Concurrently, recent translational and preclinical research have provided insights into novel immune, molecular and metabolic features of MBM that mediate the aggressive biology and therapeutic resistance of these tumors. In this systematic review, we review the etiopathogenesis of MBM, and describe the various therapeutics options available with a focus on new paradigms for therapeutic interventions in MBM. We present the following article in accordance with the Narrative Review reporting checklist (available at