Concurrent intrathecal and intravenous nivolumab for metastatic melanoma patients with leptomeningeal disease.

Abstract There is a critical need for effective treatments for leptomeningeal disease (LMD). We conducted a single-arm, first-in-human phase I/Ib study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in melanoma patients with LMD. The primary endpoints were determination of safety and the recommended IT nivolumab dose. The secondary objective was overall survival (OS). Patients were treated with IT nivolumab alone in cycle 1; IV nivolumab 240 mg was included in subsequent cycles, which were administered every two weeks. The dose escalation portion evaluated 5, 10, 20, and 50 mg of IT nivolumab. Twenty-five patients were enrolled and treated (twenty-one previously treated with anti-PD1): 2 with 5 mg, 3 with 10 mg, 14 with 20 mg, and 6 with 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level; 10 patients experienced grade 1 or 2 toxicities, possibly related to IT nivolumab. The recommended IT dose of nivolumab was 50 mg (with IV nivolumab 240 mg) every 2 weeks. The median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. Concurrent IT and IV nivolumab is safe, feasible and appears to have a preliminary efficacy signal in patients with melanoma LMD, including in patients with previous anti-PD1 therapy.