Synergistic efficacy of intrathecal PD-1 blockade combined with whole-brain radiotherapy for melanoma leptomeningeal metastases: A real-world analysis.

Abstract

e14023 Background: Leptomeningeal metastasis (LM) from malignant melanoma remains a catastrophic event with a historical median survival of <3 months. While intrathecal (IT) administration of PD-1 antibodies has shown preliminary efficacy, the potential synergy between radiotherapy-induced immunogenic cell death and compartmentalized checkpoint blockade remains unexplored. We investigated the safety and survival impact of combining WBRT with IT PD-1 antibody therapy in this high-risk population. Methods: We retrospectively analyzed consecutive patients with melanoma LM treated with IT PD-1 antibodies at a single center between June 2022 and December 2024. The cohort was stratified by treatment modality: IT Monotherapy vs. Combination Therapy (WBRT delivered within 30 days of IT PD-1 initiation). The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS), assessed by Kaplan-Meier analysis and Log-rank tests. Safety was rigorously graded per NCI-CTCAE v5.0, with specific focus on neurotoxicity and immune-related adverse events (irAEs). Results: A total of 20 patients were enrolled (Combination: n=13; Monotherapy: n=7). Baseline characteristics were well-balanced. The Combination arm achieved a striking survival advantage, with a median OS of 45.3 weeks (95% CI 28.7–NR) compared to 20.1 weeks (95% CI 13.3–NR) in the Monotherapy arm (HR 0.30 [95% CI, 0.04-0.68]; P = 0.021). Similarly, median iPFS was more than doubled in the Combination group (23.0 vs. 10.0 weeks; P < 0.001). The regimen was well-tolerated; there was no statistically significant difference in the incidence of Grade ≥2 adverse events between groups, and no unexpected severe neurotoxicity was observed. Conclusions: Concurrent WBRT and IT PD-1 blockade demonstrates potent synergistic activity in melanoma LM, delivering unprecedented survival outcomes (median OS >10 months) without amplifying toxicity. These findings suggest that radiotherapy may prime the CSF microenvironment for enhanced immune checkpoint efficacy. This novel multimodal strategy warrants validation in prospective randomized trials as a potential new standard of care.