Abstract
<title>Abstract</title> <p> Purpose This study evaluates the efficacy and safety of furmonertinib combined with intrathecal chemotherapy at different doses in patients with leptomeningeal metastasis(LM) from non-small cell lung cancer(NSCLC). We analyze factors influencing treatment efficacy and measure furmonertinib concentrations in the cerebrospinal fluid, thereby providing a reference for precision pharmacotherapy in these patients. Methods Patients who received furmonertinib combined with intrathecal chemotherapy at our Department of Neurology from June 2023 to December 2024 were included. Medication regimens and clinical data were recorded. Cerebrospinal fluid samples were collected for furmonertinib concentration measurement. Treatment response was assessed using RANO-LM criteria, with progression-free survival as the primary endpoint. Survival outcomes were analyzed using the Kaplan–Meier method, and correlations were examined using Spearman's rank correlation coefficient. Adverse events during treatment were documented. The effects of different treatment options and clinical characteristics on efficacy were also analyzed. Results Totally 70 patients were included. The objective response rate (ORR) was 22.8%, and the disease control rate (DCR) was 91.3%. Median progression-free survival (mPFS) was 186 days (95% CI: 176.16–195.84). Mild adverse events of grade 1–2 occurred in 38 patients (54.3%), while grade 3–4 adverse events were observed in 5 patients (7.14%). Univariate analysis revealed that an ECOG score ≤ 2 and the use of pemetrexed for intrathecal chemotherapy (vs. methotrexate) were associated with improved progression-free surviva PFS (both P < 0.05). Multivariate Cox regression analysis identified ECOG score as an independent prognostic factor. In the subgroup analysis of patients previously treated with third-generation TKIs, both furmonertinib dosage and concurrent use of antiangiogenic agents were correlated with PFS. Furmonertinib cerebrospinal fluid (CSF) concentration was strongly positively correlated with CSF protein content (Spearman’s ρ = 0.66, <italic>P <</italic> 0.01). Conclusion Furmonertinib combined with intrathecal chemotherapy (pemetrexed superior to methotrexate) prolonged PFS in EGFR-mutant NSCLC patients with LM, with a manageable safety profile. ECOG performance status was identified as an independent prognostic factor. Among patients previously treated with third-generation TKIs, the combination of furmonertinib 160 mg once daily with antiangiogenic therapy yielded longer PFS. Cerebrospinal fluid concentration measurements suggested that the degree of blood–brain barrier disruption may serve as a rate-limiting factor for furmonertinib penetration into the cerebrospinal fluid. </p>