[Efficacy and Safety of High-dose Furmonertinib plus Intrathecal Pemetrexed for EGFR-mutant Non-small Cell Lung Cancer with Leptomeningeal Metastasis].

内容摘要

Leptomeningeal metastasis (LM) is a devastating complication of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), with a poor prognosis. While high-dose third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can enhance drug concentrations in the central nervous system, their efficacy as monotherapy remains limited. Intrathecal Pemetrexed (IP) offers a promising local treatment approach by bypassing the blood-brain barrier and acting directly within the cerebrospinal fluid. However, clinical data on the efficacy and safety of combining high-dose third-generation EGFR-TKIs Furmonertinib (160 mg/d) with IP in EGFR-mutant NSCLC-LM patients are still scarce. Therefore, this study aims to evaluate the efficacy and safety of this combination regimen in this population to provide real-world data support for clinical practice. In this retrospective study, 40 patients with EGFR-mutant NSCLC-LM were enrolled at Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University between June 2021 and December 2024. All patients received oral Furmonertinib (160 mg/d) combined with IP. Primary endpoints were intracranial progression-free survival (iPFS), overall survival (OS), overall response rate (ORR) and adverse events. Survival analysis was performed using the Kaplan-Meier method, and prognostic factors were assessed via Cox proportional hazards regression by collecting the clinical data and follow-up information of the patients. After a median follow-up of 20.0 months, the combination therapy demonstrated significant efficacy. The ORR was 85.0%, with a median iPFS of 9.6 months and a median OS of 12.6 months. The 6-, 12- and 24-month OS rates were 79.9%, 53.9% and 27.0%, respectively. Multivariate analysis identified combination therapy with Bevacizumab as an independent protective factor [hazard ratio (HR)=0.283, 95%CI: 0.114-0.702, P=0.006], while a poor baseline Karnofsky performance status (KPS) score was an independent risk factor (HR=3.069, 95%CI: 1.313-7.170, P=0.010). Adverse events were primarily grade 1-2, including myelosuppression (42.5%), elevated transaminases (22.5%), and gastrointestinal reactions (nausea and/or vomiting, 20.0%). Only one case of grade 4 myelosuppression was reported and resolved after supportive care. High-dose Furmonertinib combined with IP is an effective and well-tolerated regimen for EGFR-mutant NSCLC-LM. The addition of Bevacizumab may further improve outcomes, offering a promising strategy for refractory patients. 【中文题目：高剂量伏美替尼联合培美曲塞鞘内化疗治疗EGFR突变型非小细胞肺癌软脑膜转移
的疗效与安全性分析】 【中文摘要：背景与目的 软脑膜转移（leptomeningeal metastasis, LM）是表皮生长因子受体（epidermal growth factor receptor, EGFR）突变型非小细胞肺癌（non-small cell lung cancer, NSCLC）的严重并发症，预后极差。第三代EGFR-酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitors, EGFR-TKIs）增加剂量虽可提升中枢神经系统药物浓度，但其单药疗效仍不足以有效控制疾病进展。培美曲塞鞘内注射（intrathecal Pemetrexed, IP）能够绕过血脑屏障，直接作用于脑脊液，为LM的局部治疗提供了新途径。然而，目前关于高剂量第三代EGFR-TKIs伏美替尼（160 mg/d）联合IP治疗EGFR突变型NSCLC-LM的临床疗效与安全性的研究数据仍较缺乏。因此，本研究旨在评估该联合方案在此类难治性患者中的有效性及安全性，以期为临床实践提供真实世界证据。方法 选择2021年6月至2024年12月南京大学医学院附属鼓楼医院收治的40例EGFR突变型NSCLC-LM患者，其治疗方案均为高剂量伏美替尼（160 mg/d）联合IP治疗。通过系统收集患者的临床病例资料及随访信息，分析其颅内无进展生存期（intracranial progression-free survival, iPFS）和总生存期（overall survival, OS）、总体反应率和不良事件。生存分析采用Kaplan-Meier法，预后影响因素通过Cox比例风险回归进行多变量分析。结果 中位随访时间20.0个月，高剂量伏美替尼联合IP治疗在EGFR突变型NSCLC-LM患者中展现出显著疗效：总体反应率为85.0%，iPFS为9.6个月，中位OS为12.6个月，6、12和24个月的OS率分别为79.9%、53.9%和27.0%。多因素分析表明，联合贝伐珠单抗治疗是独立的保护性预后因素［风险比（hazard ratio, HR）=0.283, 95%CI: 0.114-0.702, P=0.006］，而基线卡氏体能状态（Karnofsky performance status, KPS）评分较差是独立危险因素（HR=3.069, 95%CI: 1.313-7.170, P=0.010）。安全性方面，主要不良事件为骨髓抑制（42.5%）、转氨酶升高（22.5%）和消化道反应（恶心和/或呕吐20.0%），多数为1-2级。仅报告1例4级骨髓抑制，经支持治疗后好转。结论 高剂量伏美替尼联合IP在EGFR突变型NSCLC-LM患者中表现出显著疗效和可控的安全性，联合贝伐珠单抗可能进一步增加临床获益，为难治性患者提供了有前景的治疗策略。
】 【中文关键词：肺肿瘤；软脑膜转移；表皮生长因子受体；伏美替尼；培美曲塞鞘内化疗】.