Intrathecal immune checkpoint inhibitors as adjunctive therapy for leptomeningeal disease: A case series and systematic review.

Immune checkpoint inhibitors (ICIs) are promising for leptomeningeal disease (LMD), but systemic delivery is limited by poor cerebrospinal fluid penetration and treatment-related toxicity. This study evaluates the safety and efficacy of adjunctive intrathecal (IT) ICI therapy compared with systemic ICI alone. We report two institutional cases of melanoma-associated LMD treated with IT ICI alongside systemic therapy. Following PRISMA guidelines, PubMed, Embase, and Scopus were systematically reviewed, identifying 28 eligible studies consisting of case reports, small series, and early phase trials. Of 542 patients screened, 201 received ICI therapy: 161 systemic ICI alone and 40 IT ICI with concurrent systemic therapy. Patient-level and aggregate data were extracted to compare adverse events (AEs), progression-free survival (PFS), and overall survival (OS). Exploratory time- and dose-adjusted analyses accounted for differences in treatment exposure. IT ICI therapy demonstrated a favorable safety profile. At the patient level, adjunct IT delivery was associated with a non-significant trend toward reduced grade ≥ 3 AE risk (RR 0.50; 95% CI, 0.22-1.13; p = 0.096). At the event level, adjunct IT therapy was significantly associated with 72% fewer grade ≥ 3 AEs per patient (rate ratio 0.28; 95% CI, 0.12-0.64; p = 0.003). Dose-adjusted meta-regression suggested cumulative exposure did not explain these differences. No significant differences were observed in PFS or OS after multivariable adjustment. Adjunct IT ICI therapy was not associated with increased adverse event risk or high-grade toxicity burden compared with systemic ICI alone, supporting its feasibility as an adjunctive therapeutic strategy for LMD that warrants prospective evaluation.