Furmonertinib联合贝伐单抗治疗EGFR-TKI耐药软脑膜转移：脑脊液ctDNA分子反应和生存结果分析
Furmonertinib combined with bevacizumab in EGFR-TKI-resistant leptomeningeal metastasis: analysis of the CSF ctDNA molecular response and survival outcomes.
摘要(中文译文)
第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药性发展后的瘦素转移（LM）表明EGFR突变型非小细胞肺癌（NSCLC）预后不良，目前尚无标准化治疗方法。本研究的目的是评估在这种情况下贝伐单抗联合高剂量弗莫尼替尼治疗的结果，并评估脑脊液（CSF）循环肿瘤DNA（ctDNA）分子反应作为治疗反应生物标志物。这项现实世界的研究包括104名在接受第三代TKI治疗后出现LM进展的EGFR突变型NSCLC患者。队列1（n = 62) 接受了呋莫尼替尼（160mg）+贝伐单抗的联合治疗，队列2（n = 42) 接受呋莫尼替尼（160mg）单药治疗。主要终点是颅内无进展生存期（iPFS）和总生存期（OS）。在CSF ctDNA纵向分析中，分子反应定义如下：ΔctDNA ≤ 0.8 × 基线。与单药治疗相比，贝伐单抗联合大剂量弗莫尼替尼治疗显著改善了LM反应（中位iPFS:6.77 vs 4.04个月，95%CI:0.41-0.98，p = 0.038;中位OS：分别为15.31个月和7.10个月，95%置信区间：0.29-0.82，p = 0.002). 脑脊液ctDNA分析显示，31/47名患者（66%）达到了分子反应；与未接受治疗的患者相比，接受治疗的人的生存期显著延长（iPFS:8.94个月vs 6.67个月（HR = 0.40,95%置信区间：0.21-0.79）；OS：分别为20.44个月和8.71个月（HR = 0.34,95%置信区间：0.14-0.83）。ctDNA在两个时间点的纵向下降与生存益处进一步相关（iPFS:9.96 vs 7.33个月（HR = 0.42, p = 0.01);OS：25.63个月vs.15.31个月，（HR = 0.28, p = 0.03)). 贝伐单抗与高剂量弗莫尼替尼协同作用，显著改善TKI耐药LM的生存结果。脑脊液ctDNA分子反应阳性（ΔctDNA ≤ 0.8 × 基线）可以预测临床效益，支持其实时监测的实用性。这种联合疗法代表了一种治疗需求未得到满足的人群的有前景的策略。
Abstract
Leptomeningeal metastasis (LM) after the development of third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is indicative of a poor prognosis in EGFR-mutant non-small cell lung cancer (NSCLC), and no standardised treatments are currently available. The aims of this study were to evaluate the outcomes of combination therapy with bevacizumab plus high-dose furmonertinib in this setting and to assess the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) molecular response as a treatment response biomarker. This real-world study included 104 patients with EGFR-mutant NSCLC who experienced LM progression after treatment with third-generation TKIs. Cohort 1 (n = 62) received combination therapy with furmonertinib (160 mg) + bevacizumab, and Cohort 2 (n = 42) received furmonertinib (160 mg) monotherapy. The primary endpoints were intracranial progression-free survival (iPFS) and overall survival (OS). In the longitudinal CSF ctDNA analysis, a molecular response was defined as follows: ΔctDNA ≤ 0.8 × baseline. Combination therapy with bevacizumab plus high-dose furmonertinib significantly improved the LM response compared to that of furmonertinib monotherapy (median iPFS: 6.77 vs 4.04 months, respectively, 95% CI: 0.41-0.98, p = 0.038; median OS: 15.31 vs 7.10 months, respectively, 95% CI: 0.29-0.82, p = 0.002). The CSF ctDNA analysis revealed that 31/47 patients (66%) achieved a molecular response; those that did experienced significantly prolonged survival outcomes compared to those of patients who did not (iPFS: 8.94 vs 6.67 months, respectively (HR = 0.40, 95% CI: 0.21-0.79); OS: 20.44 vs 8.71 months, respectively (HR = 0.34, 95% CI: 0.14-0.83)). A longitudinal decline in ctDNA across two time points further correlated with survival benefits (iPFS: 9.96 vs 7.33 months (HR = 0.42, p = 0.01); OS: 25.63 vs.15.31 months, (HR = 0.28, p = 0.03)). Bevacizumab synergises with high-dose furmonertinib to significantly improve survival outcomes in TKI-resistant LM. A positive CSF ctDNA molecular response (ΔctDNA ≤ 0.8 × baseline) is predictive of clinical benefits, supporting its utility for real-time monitoring. This combination therapy represents a promising strategy for the treatment of a population with unmet needs.
如何引用
AMA
Xiaoyue Wang, Yuwen Xie, Jin Hu, Na Liu, Liangfeng Yang, Ting Xu, et al. Furmonertinib combined with bevacizumab in EGFR-TKI-resistant leptomeningeal metastasis: analysis of the CSF ctDNA molecular response and survival outcomes.. British journal of cancer. 2026; doi:10.1038/s41416-026-03407-z.
APA
Xiaoyue Wang, Yuwen Xie, Jin Hu, Na Liu, Liangfeng Yang, Ting Xu, et al (2026). Furmonertinib combined with bevacizumab in EGFR-TKI-resistant leptomeningeal metastasis: analysis of the CSF ctDNA molecular response and survival outcomes.. British journal of cancer. https://doi.org/10.1038/s41416-026-03407-z
GB/T 7714
Xiaoyue Wang, Yuwen Xie, Jin Hu, Na Liu, Liangfeng Yang, Ting Xu, et al. Furmonertinib combined with bevacizumab in EGFR-TKI-resistant leptomeningeal metastasis: analysis of the CSF ctDNA molecular response and survival outcomes.[J]. British journal of cancer, 2026 doi:10.1038/s41416-026-03407-z.
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