Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results

• Published in: Nature medicine Vol. 29; no. 4; pp. 898 - 905
• Main Authors: Glitza Oliva, Isabella C., Ferguson, Sherise D., Bassett, Roland, Foster, Alexandra P., John, Ida, Hennegan, Tarin D., Rohlfs, Michelle, Richard, Jessie, Iqbal, Masood, Dett, Tina, Lacey, Carol, Jackson, Natalie, Rodgers, Theresa, Phillips, Suzanne, Duncan, Sheila, Haydu, Lauren, Lin, Ruitao, Amaria, Rodabe N., Wong, Michael K., Diab, Adi, Yee, Cassian, Patel, Sapna P., McQuade, Jennifer L., Fischer, Grant M., McCutcheon, Ian E., O’Brien, Barbara J., Tummala, Sudhakar, Debnam, Matthew, Guha-Thakurta, Nandita, Wargo, Jennifer A., Carapeto, Fernando C. L., Hudgens, Courtney W., Huse, Jason T., Tetzlaff, Michael T., Burton, Elizabeth M., Tawbi, Hussein A., Davies, Michael A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2023; Nature Publishing Group
• Subjects: 692/308/2779/109/1940; 692/699/67/1059/2325; 692/699/67/1813/1634; 692/699/67/1922; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biomedical and Life Sciences; Biomedicine; Cancer Research; Constraining; Humans; Infectious Diseases; Intravenous administration; Ipilimumab; Lung cancer; Lung Neoplasms - drug therapy; Melanoma; Melanoma - pathology; Meninges; Metabolic Diseases; Metastases; Molecular Medicine; Neurosciences; Nivolumab; PD-1 protein; Treatment Outcome
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-022-02170-x

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 . In an interim analysis of a phase 1 trial of concurrent intrathecal and intravenous anti-PD1 delivery in patients with leptomeningeal disease and melanoma, treatment was feasible and well-tolerated with no dose-limiting toxicities.