INNV-42. Survival benefit of targeted therapy in EGFR-mutant NSCLC patients with leptomeningeal metastases

Abstract BACKGROUND Leptomeningeal disease (LMD) is a rare but devastating complication of non-small cell lung cancer (NSCLC), particularly in patients with EGFR mutations. Its natural history is marked by neurologic decline and poor survival, with historical median overall survival (OS) of less than six months. Recent advances in EGFR-targeted therapies—especially third-generation tyrosine kinase inhibitors (TKIs)—have improved CNS penetration, raising the possibility of extended survival even in LMD. However, aggregate survival outcomes remain undercharacterized. METHODS We performed a meta-analysis to evaluate survival outcomes in EGFR-mutant NSCLC patients with confirmed LMD treated with systemic EGFR-targeted therapies. PubMed, Embase, and Cochrane CENTRAL were searched through April 2025. Eligible studies reported median OS and included EGFR-targeted treatment. Median OS values were log-transformed and pooled using a random-effects model, with heterogeneity assessed via Q, τ², and I² statistics. RESULTS A total of 11 studies comprising 543 patients with EGFR-mutant NSCLC and LMD were included. The median patient age was 58.0 years (IQR: 56.5–59.0), and 36.7% were male. Prior radiotherapy was reported in 34.6% of patients, and prior systemic therapy in 36.0%. All patients received EGFR-targeted systemic therapy, most commonly third-generation TKIs. The interventions included Afatinib, Erlotinib, Furmonertinib, Gefitinib, Osimertinib, and Rociletinib. In the meta-analysis, the pooled log-median OS was 2.362 (95% CI: 2.163–2.561), corresponding to an estimated median OS of 10.6 months. Heterogeneity was moderate (I²=27.4%, Q=5.51, P=0.239), and publication bias was insignificant. The median follow-up duration was 9.6 months (IQR: 7.8–11.1). CONCLUSIONS This meta-analysis provides the first pooled survival estimate in EGFR-mutant NSCLC patients with LMD receiving targeted therapies. The findings suggest that modern EGFR TKIs may offer clinically meaningful survival benefits in this otherwise high-risk group. Prospective studies are needed to validate these results and to define optimal treatment strategies.