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9522 Background: The prognosis of melanoma patients with leptomeningeal disease (LMD) remains poor (median OS of 3.5 months). Intrathecal (IT) drug administration could bypass the blood-cerebrospinal fluid (CSF) barrier and has been explored in many cancers using chemotherapies or monoclonal antibodies. According to a recent phase I trial (PMID36997799), nivolumab IT delivery appears safe while its efficacy remains to be further investigated. Methods: We retrospectively reviewed melanoma patients with LMD treated with continuous IT administration of nivolumab (after decision in multidisciplinary tumor boards) at 2 institutions from February 2021 to October 2023. Patients received 10 to 13.5 mg/day of IT nivolumab delivered through a catheter (cath) connected to an implanted pump. Nivolumab concentrations were monitored in spinal CSF via an independent access port. All patients were enrolled in the MelBase cohort. Results: 11 patients (5 females, median age 52) were treated with continuous IT nivolumab with median (IQR) time to follow-up of 2.5 (1.1-6.3) months (m). Nivolumab was delivered through a spinal (n=10) and ventricular (n=1) cath. All patients had progressed on systemic immunotherapy (ipilimumab + nivolumab n=10, nivolumab n=1). Five patients had symptomatic LMD. All patients were ECOG 0 or 1 except one patient ECOG 3 (due to neurological deficit). Primary tumors were cutaneous (n=8), mucosal (n=1) and unknown (n=2). Tumors were BRAFV600 (n=10) and NRASQ61-mutated (n=1). All but 3 patients had stable extracranial disease. Concomitant systemic therapies were the following: corticosteroids (n=5), intravenous nivolumab (first 3 months of IT therapy) (n=1), and targeted therapies (n=4). The median duration of IT treatment was 1.5 (0.5-2.7) m. The median overall survival (OS) was 2.5 (1.1-NA) m. OS at 3, 12 and 19 m were 36.4 % (16.6-79.5), 27.3 % (10.4-71.6) and 13.6 % (10.4-71.6), respectively. Three patients had prolonged survival (19 m n=2, 12 m n=1). Treatment-related adverse events (all reversible) occurred in 5 patients: hemorrhage on cath path (n=1, grade 2), immune-mediated meningoencephalitis (n=1, grade 3), intracranial hypotension syndrome (n=3, grade 2). Steady state was obtained after 3 weeks of continuous IT infusion. Pharmacokinetics data are summarized in Table. Conclusions: Survival data are slightly inferior to those previously published. However 3 patients had prolonged survival (>=1 year). Median nivolumab concentrations in CSF were comparable to through plasma concentrations at steady state after 3mg/kg IV infusion. High plasma concentrations suggest rapid clearance of nivolumab from the CSF, possibly related to reverse transcytosis of immunoglobulins. Table: see text
Faillot et al. (Sat,) studied this question.