Abstract 1155: Highly CNS-penetrant tyrosine kinase inhibitors improve leptomeningeal overall survival in NSCLC patients with leptomeningeal disease

Background: As survival rates in lung cancer patients continue to improve, leptomeningeal disease (LMD) has emerged as a critical area of unmet need, representing a devastating complication of NSCLC. CNS-penetrating tyrosine kinase inhibitors (TKIs) were developed for treating brain parenchymal metastases, but their roles in treating LMD are less defined. Even less is known about the benefits of other therapeutic approaches, including immunotherapy, radiation therapy, and intrathecal therapies, in managing LMD from NSCLC. Methods: THRILLS-NSCLC is a global (USA, China, and Europe), multi-center retrospective analysis of 592 LMD NSCLC patients evaluating their disease and treatment course. We aim to understand diagnostic patterns, clinical characteristics and outcomes of LMD in NSCLC, and to determine the potential benefit of different treatment modalities. The primary end point was leptomeningeal overall survival (LMOS). Key secondary end points were other clinical outcomes analyzed by clinical characteristics, treatment strategies, and EGFR mutation status. Results: Of the 592 patients, 66% had tumors with EGFR mutations, while 17% had no identifiable oncogene drivers. Patients were diagnosed with CSF cytology (39%) and/or brain MRI (96%), with most patients (86%) experiencing neurological symptoms. The median overall survival following LMD diagnosis (LMOS) was 8.3 months (95% CI 7.1-9.6 months). Treatment with a highly CNS-penetrant TKI after LMD diagnosis was associated with a significant improvement in LMOS, 14.2 months (95% CI 11.8-16.6), compared to 7.3 months (95% CI, 5.2-9.5) among those who received other systemic therapies (HR 0.56, 95% CI 0.40-0.80, p < 0.001). Multivariate analysis also identified CNS radiotherapy, ECOG performance status <2, female gender, Asian race, and non-squamous histology as factors associated with prolonged LMOS. Among 391 patients with EGFR-mutant NSCLC and LMD, the use of CNS-penetrant TKIs (e.g., osimertinib) after LMD diagnosis remained a significant factor associated with improved survival. The incidence of LMD was approximately 4.6% across all EGFR-mutant NSCLC patients in this analysis. Conclusions: In this largest international cohort of LMD in NSCLC patients, treatment with a CNS-penetrant TKI and CNS radiation were associated with longer LMOS, underscoring the critical role of highly CNS-penetrating TKIs in treating LMD from tumors with driver mutations and highlighting the pressing need for more effective therapies for this patient population. Citation Format: Xiuning Le, Kelsey Pan, Jianjun Zhang, Fangdi Sun, Maxime Borgeaud, Jonathan Riess, Nathaniel Myall, Yang Xia, Alfredo Addeo, John V. Heymach. Highly CNS-penetrant tyrosine kinase inhibitors improve leptomeningeal overall survival in NSCLC patients with leptomeningeal disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1155.