IntroductionLeptomeningeal metastasis (LM) is one of the most severe complications of non-small cell lung cancer (NSCLC). Furmonertinib is a pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with a high rate of brain penetration and a wide therapeutic window. Here, we evaluated the efficacy and safety of high-dose furmonertinib in patients with EGFR-mutated NSCLC and LM. MethodsThis prospective real-world study included patients with EGFR-mutated NSCLC and LM treated with a high-dose furmonertinib (240 mg once daily) as a monotherapy or in combination with other treatments. The primary endpoint was overall survival (OS), and the secondary endpoints included time to treatment discontinuation (TTD) and clinical response rate. Additional efficacy evaluations included changes in brain magnetic resonance imaging (MRI) by the RANO-LM radiologic criteria. We also introduced next generation sequencing (NGS)-based assays to evaluate genomic and epigenomic features of cell-free DNA (cfDNA) in patients’ cerebrospinal fluid (CSF) samples and to analyze their associations with patient outcomes. ResultsWe enrolled 48 patients, of whom 35 (72.9%) had received third-generation EGFR-TKIs. The median OS was 8.43 months (95%CI, 5.48 to 11.39 months), while the median TTD was 8.27 months (95%CI, 5.40 to 11.14 months), and the clinical response rate was 75%. The LM objective response rate (ORR) and disease control rate (DCR) assessed with RANO-LM radiologic criteria were 50.0% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. Briefly, 22 (45.8%) had adverse events (AEs) possibly related to furmonertinib and three (6.3%) had a grade 3-elevated aminotransaminase or nausea or leucopenia, leading to dose reduction to 160 mg daily. Furthermore, methylation analysis of cfDNA in CSF showed that there was a significant correlation between the changes of aberrant methylated fragments (AMFs) from lung cancer cells and the response of the patients. Meanwhile, the copy number burden (CNB) scores derived from the low-pass whole genome sequencing (LP-WGS) assay may offer another objective and effective method for the diagnosis and evaluation of treatment efficacy in LM. ConclusionIn the real world, the high-dose furmonertinib-based treatment may potentially have clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients previously treated with other third-generation EGFR-TKIs. Methylation and CNB analysis of cfDNA in CSF may be considered objective indicators for the diagnosis of LM and evaluation of treatment response.