脑室内化疗联合伏美替尼加倍剂量及贝伐珠单抗治疗三代EGFR-TKIs耐药肺癌软脑膜转移临床研究

Treatment of third-generation EGFR-TKIs resistant lung cancer with leptomeningeal metastasis using intraventricular chemotherapy combined with doubled dose of famotinib and bevacizumab monoclonal antibody

目的探讨脑室内化疗和伏美替尼加倍剂量联合或者不联合贝伐珠单抗治疗三代表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKIs)耐药后的非小细胞肺癌(NSCLC)伴软脑膜转移(LM)的疗效和安全性。方法回顾性收集2021-09-01-2023-05-31南京医科大学附属脑科医院收治的68例三代EGFR-TKIs耐药后的NSCLC伴LM患者的临床资料。观察组40例患者接受脑室内化疗(培美曲塞30或50 mg)和伏美替尼加倍剂量(160 mg,口服,1次/d)联合贝伐珠单抗治疗,对照组28例患者仅接受脑室内化疗和伏美替尼加倍剂量治疗。主要根据神经肿瘤评价标准(RANO)评估软脑膜转移瘤的治疗效果,生存分析采用Kaplan-Meier法并行log-rank检验。根据常见不良事件评价标准(CTCAE)5.0版评估不良反应。结果根据RANO标准进行软脑膜转移瘤的疗效评价,30例(44.1%)有效,31例(45.6%)稳定,7例(10.3%)进展。观察组中20例(50.0%)有效,18例(45.0%)稳定,2例(5.0%)进展;对照组中10例(35.7%)有效,13例(46.4%)稳定,5例(17.9%)进展,2组有效率比较差异无统计学意义,χ^(2)=3.414,P=0.181。头颅增强MRI显示好转32例(47.1%),稳定30例(44.1%),进展6例(8.8%)。总人群的中位颅内无进展生存期(iPFS)为7.6个月,对照组和观察组的中位iPFS分别为4.6和11.6个月(HR=2.724,95%CI:1.425~5.207,χ^(2)=10.003,P=0.002)。总人群的中位OS未达到,其中对照组和观察组的中位OS分别为8.8个月和未达到(HR=4.391,95%CI:1.606~12.001,χ^(2)=9.930,P=0.002)。160 mg伏美替尼常见不良反应是皮疹和腹泻,贝伐珠单抗常见不良反应包括出血和蛋白尿,侧脑室内注射培美曲塞最常见的不良反应为骨髓抑制和无菌性脑膜炎,2组间差异均无统计学意义,均P>0.05。结论脑室内化疗和伏美替尼加倍剂量联合贝伐珠单抗能够提高NSCLC伴LM患者的生活质量,明显延长生存时间,且不良反应可控,安全性可靠。

Objective To assess the efficacy and safety of intraventricular chemotherapy and double dose of furmonertinib with or without bevacizumab,in treating leptomeningeal metastasis(LM)from non-small cell lung cancer(NSCLC)resistant to third-generation epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)targeted therapies.Methods The study retrospectively included 68 NSCLC-LM patients who developed resistance after third-generation EGFR-TKIs at the Affiliated Brain Hospital of Nanjing Medical University from September 1,2021 to May 31,2023.40 patients received intraventricular chemotherapy(30 mg or 50 mg pemetrexed)and double dose of furmonertinib(160 mg 0-rally daily)combined with bevacizumab in the observation group,and 28 patients in the control group received only intraventricular chemotherapy and double dose of furmonertinib.Response Assessment in Neuro-Oncology(RANO)were used to evaluate the assessment of LM response.All adverse events were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events,version 5.O.Clinical outcomes were compared with the Kaplan-Meier log-rank test.Results Based on RANO criteria,30(44.1%)patients had responsive disease and 31(45.6%)patients had stable disease,seven patients(10.3%)developed progressive disease.The observation group had 20(50.0%)responsive disease,18(45.0%)stable disease and 2(5.0%)progressive disease,while the control group had 10(35.7%)responsive disease,13(46.4%)stable disease and 5(17.9%)progressive disease.However,there was no statistically significant dfference in the effective rate between the two groups,χ^(2)=3.414,P=0.181.Enhanced MRI showed improvement in 32(47.1%)patients,stability in 30(44.1%)patients,and progression in 6(8.8%)patients.The median intracranial progression-free survival(iPFS)in the entire group was 7.6 months,and the median iPFS was 4.6 and 11.6 months,respectively in the control and observation groups(HR=2.724,95%CI:1.425-5.207.χ^(2)=10.003,P=0.002).The median overall survival(OS)in the control group was 8.8 months,the observation group was not reached(HR=4.391,95%CI:1.606-12.001,χ^(2)=9.930,P=0.002).The most common adverse events of 160 mg furmonertinib were rash and diarrhea,the common side effects of bevacizumab included bleeding and proteinuria,and myelosuppression and aseptic meningitis were the main adverse reactions of intraventricular chemotherapy.There was no statistical difference between the two groups.Conclusion Intraventricular chemotherapy and double dose of furmonertinib combined with bevacizumab can improve the quality of life and prolong the survival time in NSCLC patients with LM,with a manageable safety profile.