Objective: To explore the prognosis of patients with leptomeningeal metastasis (LM) and epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC) treated with different kinds of tyrosine kinase inhibitors (TKIs). Methods: From January 2016 to June 2021, the clinicopathological data of 70 patients confirmed by histologically or cytologically EGFRm LM who received different types of TKIs in Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively analyzed. According to treatment patterns, patients were divided into the first-and second-generation EGFR-TKIs treatment group and the third-generation EGFR-TKIs treatment group [Osimertinib 80 mg once a day], and the prognosis and prognostic factors (with Cox proportional hazards model) of patients in different treatment group were assessed. The next-generation sequencing (NGS) of paired samples of cerebrospinal fluid (CSF) and plasma from 64 patients at the time of LM diagnosis was performed simultaneously. Results: There were 20 males and 50 females in 70 EGFRm NSCLC patients with LM. The age ranged from 35 to 69 years, with a median age of 56 years. A total of 24 patients received the first-and second-generation EGFR-TKIs treatment, and 46 received the third-generation EGFR-TKIs treatment. Twenty-four patients developed disease progression on the first-and second EGFR-TKIs treatments, followed by treatment with the third-generation EGFR-TKIs (Osimertinib) in 12 cases, chemotherapy or anti-angiogenesis therapy in 4 cases, and the optimal supportive treatment in 8 cases. Among the 70 patients, 18 had partial response (PR), 48 had stable disease (SD), and 4 had progressive disease (PD). The objective response rate (ORR) and disease control rate (DCR) were 26% (18/70) and 94% (66/70), respectively. The median follow-up time was 16.5 months. The median progression-free survival (PFS) was 5.3 months(95%CI: 2.8-7.8)in the first-and second-generation EGFR-TKIs and 10.8 months (95%CI: 7.9-13.6) in the third-generation EGFR-TKIs, and the difference was statistically significant (P=0.019). The median overall survival (OS) was 14.9 months (95%CI: 9.7-20.0) and 15.7 months (95%CI: 13.3-18.1) in the two groups, respectively, but no statistical differences was observed (P=0.713). Univariate analysis showed that the PFS of patients with EGFRm LM were related to gender and different types of EGFR-TKIs (P˂0.05). Multivariate analysis demonstrated that male (HR=2.30, 95%CI: 1.31-4.03, P=0.004) and the first-and second-generation EGFR-TKIs (HR=2.03, 95%CI: 1.20-3.41, P=0.008) were independent risk factors for PFS in patients with EGFRm LM. The EGFR mutation was detected in 61 (95%) CSF and in 27 (42%) plasma samples. Conclusion: In EGFRm NSCLC patients with LM, the dose of Osimertinib 80 mg (once a day) has a significant PFS benefit compared with the first-and second-generation EGFR-TKIs.
目的： 探讨不同酪氨酸激酶抑制剂（TKIs）治疗表皮生长因子受体（EGFR）突变非小细胞肺癌（NSCLC）脑膜转移（LM）患者的预后。 方法： 回顾性分析2016年1月至2021年6月在中国医学科学院肿瘤医院采用不同TKIs治疗经组织学或细胞学确诊的70例EGFR突变NSCLC伴LM患者的临床病理资料，按治疗方式分为第一和第二代EGFR-TKIs治疗组以及第三代EGFR-TKIs治疗组［奥希替尼80 mg（1次/d）］，分析不同治疗组患者的预后，以Cox单因素和多因素回归分析预后影响因素。采用二代测序法对64例患者LM确诊时的脑脊液和血浆配对样本进行基因检测。 结果： 70例EGFR突变NSCLC伴LM患者中，男20例，女50例；年龄35~69岁，中位年龄56岁；接受第一和第二代EGFR-TKIs治疗24例，接受第三代EGFR-TKIs治疗46例。24例患者接受第一和第二代EGFR-TKIs治疗后出现疾病进展，后续接受第三代EGFR-TKIs（奥希替尼）治疗12例，接受化疗或抗血管生成治疗4例，接受最佳支持治疗8例。70例患者中，部分缓解18例，疾病稳定48例，疾病进展4例，客观缓解率和疾病控制率分别为26%（18/70）和94%（66/70）。中位随访16.5个月，第一和第二代EGFR-TKIs治疗组患者的中位无进展生存时间（PFS）为 5.3个月（95%CI：2.8~7.8个月），第三代EGFR-TKIs治疗组患者的中位PFS为10.8个月（95%CI：7.9~13.6个月），差异有统计学意义（P=0.019）。第一和第二代EGFR-TKIs治疗组患者的中位总生存时间（OS）为14.9个月（95%CI：9.7~20.0个月），第三代EGFR-TKIs治疗组患者的中位OS为15.7个月（95%CI：13.3~18.1个月），差异无统计学意义（P=0.713）。单因素分析显示，EGFR突变LM患者的PFS与性别、不同种类EGFR-TKIs治疗有关（均P<0.05）；多因素分析显示，男性（HR=2.30，95%CI：1.31~4.03，P=0.004）、第一和第二代EGFR-TKIs治疗（HR=2.03，95%CI：1.20~3.41，P=0.008）是影响EGFR突变LM患者PFS的独立危险因素。61例（95%）脑脊液样本和27例（42%）血浆样本中检测到EGFR突变。 结论： 对于EGFR突变NSCLC伴LM患者，采用奥希替尼80 mg（1次/d）比第一和第二代EGFR-TKIs治疗有明显的PFS获益。.