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Background <p>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.</p> Methods <p>This real-world study included 104 patients with EGFR-mutant NSCLC who experienced LM progression after treatment with third-generation TKIs. Cohort 1 (<i>n</i> = 62) received combination therapy with furmonertinib (160 mg) + bevacizumab, and Cohort 2 (<i>n</i> = 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.</p> Results <p>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, <i>p</i> = 0.038; median OS: 15.31 vs 7.10 months, respectively, 95% CI: 0.29–0.82, <i>p</i> = 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, <i>p</i> = 0.01); OS: 25.63 vs.15.31 months, (HR = 0.28, <i>p</i> = 0.03)).</p> Conclusion <p>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.</p>

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Furmonertinib combined with bevacizumab in EGFR-TKI-resistant leptomeningeal metastasis: analysis of the CSF ctDNA molecular response and survival outcomes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月6日

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  • Xiaoyue Wang,
  • Yuwen Xie,
  • Jin Hu,
  • Na Liu,
  • Liangfeng Yang,
  • Ting Xu,
  • Shu Xu,
  • Chuanyong Yu,
  • Shencun Fang

摘要

Background

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.

Methods

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.

Results

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)).

Conclusion

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.