Narrative review outlines multimodal decision-making for EGFR-mutant NSCLC with leptomeningeal metastasis

Leptomeningeal metastasis (LM) represents a devastating complication in patients with EGFR-mutant non-small cell lung cancer (NSCLC) who develop resistance to tyrosine kinase inhibitors (TKIs). The management of LM after TKI resistance poses significant clinical challenges due to the heterogeneity of tumor staging, diverse resistance mechanisms, and limited penetration of systemic therapies across the blood–brain barrier (BBB). Current treatment strategies lack standardized protocols and require careful consideration of tumor burden, resistance patterns, and patient-specific factors. This narrative review systematically summarizes recent clinical studies, guidelines, and expert consensus addressing therapeutic decision-making in this setting. This review emphasizes multimodal clinical decision-making, integrating targeted therapies, intrathecal drug administration, radiotherapy, and intracranial pressure relief devices, with discussion of emerging immunological strategies. Although combining these therapies can improve neurological prognosis and survival rates for some patients, toxicity, the unpredictability of efficacy, and the logistical challenges of multidisciplinary treatment remain significant obstacles. To address this issue, we outline a clinical decision-making pathway aimed at helping physicians optimize and personalize treatment regimens. Looking ahead, improving our methods for identifying drug resistance mechanisms, optimizing central nervous system (CNS) drug delivery, and building stronger collaborative care models will be crucial for improving the prognosis of this vulnerable group.