• Mei-Mei Zheng, Yang-Si Li, Hai-Yan Tu, Hao Sun, Kai Yin, Ben-Yuan Jiang, Jin-Ji Yang, Xu-Chao Zhang, Qing Zhou, Chong-Rui Xu, Zhen Wang, Hua-Jun Chen, De-Xiang Zhou, and Yi-Long Wu.
• School of Medicine, South China University of Technology, Guangzhou, 510006, China.
• Bmc Med. 2022 May 30; 20 (1): 197.

BackgroundDespite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM).MethodsEGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed.ResultsA total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM.ConclusionsPrivate resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective  exploration is needed.© 2022. The Author(s).

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