Leptomeningeal disease in ALK-positive NSCLC: Survival impact of third-generation ALK inhibitors.

8644 Background: As survival outcomes for patients with ALK-positive non-small cell lung cancer (NSCLC) continue to improve with successive generations of ALK tyrosine kinase inhibitors (TKIs), leptomeningeal disease (LMD) has emerged as a growing and critical area of unmet need. While next-generation ALK TKIs were developed to enhance central nervous system (CNS) penetration and improve control of parenchymal brain metastases, their role in the treatment of LMD remains less well defined. Methods: We performed a global multi-center retrospective analysis of 141 patients with a diagnosis of ALK-positive NSCLC and radiographically or cytologically confirmed LMD at 5 academic centers across the United States and China (MD Anderson Cancer Center, Zhejiang University, Guandong Lung Cancer Institute, National Cancer Centre Singapore, and Union Hospital at Tongji Medical College) between 2007-2024. Baseline clinical characteristics, treatment history, and outcomes were collected, and subgroup analyses were performed to identify clinical and treatment-related factors associated with leptomeningeal overall survival (LMOS). Results: Of the 141 patients with ALK+ NSCLC, most patients had radiographic LMD (79.4%), while 41.1% had positive CSF cytology and 59.6% were neurologically symptomatic. The median time from metastatic lung cancer to LMD diagnosis was 40.6 months among patients who were previously treated with a 3 rd generation (3G) ALK TKI (lorlatinib), compared to 23.7 months among those without prior lorlatinib treatment (p < 0.001). The median overall survival following LMD diagnosis (LMOS) was 22.5 months. Use of a 3G ALK TKI following LMD diagnosis was associated with improved LMOS in both treatment-naïve patients and those previously treated with earlier-generation TKIs. Among TKI-naïve patients, LMOS was 42.4 months with second-generation (2G) TKI alone, 49.6 months with escalation from 2G to 3G TKI, and not reached with 3G TKI alone (p < 0.001). Among patients previously treated with a 2G TKI, LMOS was significantly improved with 3G TKI (32.6 months) compared with an alternative 2G TKI (7.0 months) or no ALK TKI (6.8 months; p = 0.01). Whole-brain radiotherapy, intrathecal therapy, and VEGF inhibition were not associated with improved LMOS. On multivariable analysis, ECOG performance status < 2 and female sex were associated with prolonged LMOS. Conclusions: This study represents the largest multi-institutional analysis of LMD in patients with ALK+ NSCLC. Highly CNS-penetrant 3G ALK TKIs are associated with delayed LMD development and significantly improved survival following LMD diagnosis, whereas WBRT and intrathecal therapies confer limited benefit. These findings support the need for potent CNS-active ALK TKIs and prospective studies including patients with LMD in ALK-driven NSCLC.