Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy

Abstract

Melanoma frequently metastasizes to the brain, with CNS involvement being clinically evident in ~30% of patients (as high as 75% at autopsy). In ~5% cases melanoma cells also metastasize to the leptomeninges, the sub-arachnoid space and cerebrospinal fluid (CSF). Patients with leptomeningeal melanoma metastases (LMM) have the worst prognosis and are characterized by rapid disease progression (mean survival 8-10 weeks) and a death from neurological causes. The recent years have seen tremendous progress in the development of targeted and immune therapies for melanoma that has translated into an increased survival benefit. Despite these gains, the majority of patients fail therapy and there is a suspicion that the brain and the leptomeninges are a “sanctuary” sites for melanoma cells that escape both targeted therapy and immunologic therapies. Emerging evidence suggests that 1) Cancer cells migrating to the CNS may have unique molecular properties and 2) the CNS/leptomeningeal microenvironment represents a pro-survival niche that influences therapeutic response. In this Mini-Review we will outline the clinical course of LMM development and will describe how the intracranial immune and cellular microenvironments offer both opportunities and challenges for the successful management of this disease. We will further discuss the latest data demonstrating the potential use of BRAF inhibitors and immune therapy in the management of LMM, and will review future potential therapeutic strategies for the management of this most devastating complication of advanced melanoma.

Leptomeningeal disease in melanoma patients: An update to treatment, challenges, and future directions

“…Thus, data regarding outcomes with checkpoint inhibitors in patients with LMD are essentially limited to case reports. There is one report of a patient with metastatic melanoma and LMD who received WBRT with no improvement and then had a complete response after treatment with ipilimumab (Smalley, Fedorenko, Kenchappa, Sahebjam, & Forsyth, ). A second case report describes two melanoma LMD patients in whom systemic therapy with anti‐PD1 therapy led to neurologic improvement (Glitza & Bucheit, ).…”

Leptomeningeal disease: current diagnostic and therapeutic strategies

“…Overall, 9–25% of patients with small-cell lung cancers demonstrated LMD. CNS involvement is seen clinically in 30% of patients with melanoma, and as high as 75% at autopsy [ 11 ]. Although only 5% of patients with breast cancer develop leptomeningeal involvement, it remains the most common etiology of LMD [ 12 ].…”

Management of melanoma metastases in the brain

“…Data on the effectiveness of modern systemic treatment in the case of metastases to the meninges are limited and scientific evidence-based standards of management are lacking. Results of recently published retrospective analyses indicate that molecularly targeted therapy and immunotherapy may improve prognosis in these patients [54,55]. A phase I clinical trial (NCT03025256) is currently being conducted using nivolumab, intravenous and intrathecal, in patients with leptomeningeal disease.…”