In a first-in-human phase I/Ib study, the largest prospective clinical trial of intrathecal immunotherapy in any cancer type and the first to systematically evaluate intrathecal administration of anti-PD1, concurrent intrathecal and intravenous administration of nivolumab was safe in patients with melanoma and leptomeningeal disease up to the highest planned dose level, with no new or unexpected side effects, and established the recommended intrathecal nivolumab dose at 50 mg. In this heavily pretreated cohort, there was preliminary evidence of clinical benefit in a subset of patients, including patients previously treated with systemic anti-PD1.

The study demonstrates the feasibility of prospective clinical trials for patients with melanoma and leptomeningeal disease. The initial results support the rationale for further evaluation of intrathecal anti-PD1 in patients with leptomeningeal disease from melanoma and other cancers. The findings from an interim analysis are published by Dr. Isabella C. Glitza Oliva of the Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 30 March 2023 in the Nature Medicine

The authors wrote in the background that although recent breakthroughs with systemic therapies have shown encouraging results for patients with melanoma and extracranial disease only, as well as parenchymal melanoma brain metastases, there has been little progress for patients with leptomeningeal disease. In particular, leptomeningeal disease from melanoma is associated with a high neurological symptom burden, and the historical median overall survival (OS) is approximately 6 weeks. With recent advances in immune and targeted therapies prolonging the survival of patients with metastatic melanoma, as well as central nervous system (CNS) surveillance with magnetic resonance imaging (MRI), the overall incidence of leptomeningeal disease, often considered a late disease complication, is rising. 

The current therapeutic options for patients with melanoma and leptomeningeal disease consist of radiation, systemic therapies or a limited number of intratechal therapies. Most available data assessing outcomes have been from retrospective studies because there have been very few prospective studies conducted in this patient population. 

Based on the improved efficacy and safety of systemically administered anti-PD1 compared with IL-2, the study team hypothesised that the treatment of patients with melanoma and leptomeningeal disease with intratechal anti-PD1 would be safe and feasible. The authors first evaluated the side effects of intratechal administration of anti-PD1 in an immunocompetent mouse model. They then designed a first-in-human dose-finding study using concurrent administration of intratechal and intravenous anti-PD1. In the article published in the Nature Medicine, they reported a non-prespecified interim analysis detailing the dose escalation portion, recommended intratechal dose, safety profile and preliminary signal for efficacy of concurrent intratechal and intravenous nivolumab in patients with melanoma and leptomeningeal disease.

In this ongoing single-arm, first-in-human phase I/Ib study of concurrent intrathecal and intravenous nivolumab in patients with melanoma and leptomeningeal disease, the primary endpoints are determination of safety and the recommended intratechal nivolumab dose. The secondary endpoint is OS. Patients are treated with intratechal nivolumab alone in cycle 1 and intravenous nivolumab is included in subsequent cycles.

The study team treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of intratechal nivolumab. There were no dose-limiting toxicities at any dose level. The recommended intratechal dose of nivolumab is 50 mg with intravenous nivolumab 240 mg every 2 weeks. Median OS was 4.9 months, with 44% and 26% rates at 26 and 52 weeks, respectively. 

The authors concluded that these initial results suggest that concurrent intratechal and intravenous nivolumab is safe and feasible with potential efficacy in patients with melanoma and leptomeningeal disease, including patients who had previously received anti-PD1. Accrual to the study continues, including patients with lung cancer. The results support the feasibility of conducting prospective clinical studies in patients with melanoma and leptomeningeal disease, consistent with recent recommendations by the US Food and Drug Administration to include patients with CNS disease in clinical trials.

Funding was provided by Bristol Myers Squibb. Research reported in this publication was supported by the US National Cancer Institute of the National Institutes of Health grant. Additional funding was provided by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the MD Anderson Cancer Center Melanoma Moon Shot Program.


Glitza Oliva IC, Ferguson SD, Bassett R, et al. Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim resultsNature Medicine; Published online 30 March 2023. DOI: