Nivolumab Injected Directly Into Spinal Fluid May Be Safe and Effective for Some Patients With Melanoma Who Have Leptomeningeal Disease

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Researchers have found that a novel approach to administer intrathecal and intravenous nivolumab has proven safe and improved survival in a subset of patients who developed leptomeningeal disease from metastatic melanoma, according to a new study published by Glitza Olivia et al in Nature Medicine.

The new findings represent one of the first-in-human trials of concurrent intrathecal and intravenous nivolumab in patients with melanoma who have leptomeningeal disease.


Leptomeningeal disease is a complication of cancer—commonly derived from metastatic melanoma, lung cancer, and breast cancer—that can occur when cancer cells from primary tumors migrate into the cerebrospinal fluid and leptomeninges. These cells can quickly spread throughout the cerebrospinal fluid and cause a wide variety of neurologic symptoms. Roughly 10% of patients with stage IV melanoma are diagnosed with leptomeningeal disease.

Although there is no cure for leptomeningeal disease, treatments such as targeted therapy and immunotherapy may improve the patients’ quality of life. While immune checkpoint inhibitors are beneficial in patients with metastatic melanoma, little is known about their potential use for treating leptomeningeal disease.  

Previous Results From Intrathecal Administration

Intrathecal immunotherapy administration has been studied in other settings. A previous study published by Glitza Olivia et al in ESMO Open demonstrated that intrathecal administration of interleukin-2 in patients with leptomeningeal disease had encouraging results but was associated with serious side effects. However, the new study showed that injecting nivolumab directly into the spinal canal may increase its concentration within the cerebrospinal fluid. These antibodies cannot otherwise easily penetrate the blood-brain barrier.

“This represents a major path forward for our patients, as there is a crucial unmet clinical need for better treatments for patients with [leptomeningeal disease],” said lead study author Isabella C. Glitza Olivia, MD, PhD, MS, Associate Professor of Melanoma Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “We are encouraged by these preliminary results for a disease that has been notoriously difficult to study due to its highly aggressive nature. This approach is safe, and we’re seeing a small subset of our patients who have had outstanding results, so we hope to learn from each and every one of them,” she added.

Study Methods and Results

In the new phase I/Ib trial, the researchers enrolled 25 patients with a median age of 43 years who had mostly received prior systemic therapy—including 84% who had received immune checkpoint inhibitors, 64% who had received BRAF/MEK inhibitors, and 12% who had received chemotherapy. The dose-expansion cohort evaluated four doses of intrathecal nivolumab concurrent with a flat dose of intravenous nivolumab.

Among the 25 patients, the researchers discovered that the median overall survival was 4.9 months, with a 44% overall survival rate after 26 weeks and 26% survival rate after 52 weeks. Four patients survived to 74, 115, 136, and 143 weeks after their first intrathecal dose of nivolumab, which was significantly longer than expected.

Intrathecal nivolumab was well tolerated at its highest dose level, with only mild grade 1 or 2 side effects and no dose-limiting toxicities. The most common treatment-related adverse events were nausea, dizziness, and vomiting.


“Until recently, there have been limited resources to develop clinical trials in this space, but we owe it to patients with very challenging diseases to push the unknown and to advocate for them when they don’t have many options,” Dr. Glitza Oliva stressed. “We are optimistic that these results, along with further clinical trials, will lead us to a better understanding of [leptomeningeal disease] and, ultimately, more effective ways of helping our patients,” she concluded.

The researchers reported that they recently completed enrollment for the dose-expansion cohort and that analysis is underway to provide an opportunity for further insights. Ongoing research will seek to identify biomarkers that may predict which patients may achieve the most benefits from this treatment approach.

Disclosure: The research in this study was supported by the Bristol Myers Squibb Foundation. Additional funding was provided by the National Cancer Institute, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and The University of Texas MD Anderson Cancer Center’s Moon Shots Program. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.