Background

Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM.

Methods

We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs.

Results

The median follow-up period was 28.7 months (range 0.6–40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0–15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05).

Conclusions

High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.

中文翻译：

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大剂量第三代EGFR酪氨酸激酶抑制剂治疗EGFR突变非小细胞肺癌软脑膜转移患者的疗效

背景

软脑膜转移（LM）与表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者的极差预后相关。第三代 EGFR 酪氨酸激酶抑制剂 (TKI) 是目前的首选药物，显着改善了这些患者的治疗结果。然而，临床上第三代 EGFR-TKIs 在 NSCLC LM 患者中的最佳临床使用剂量仍未确定。

方法

我们回顾性分析了 105 例 EGFR 突变 NSCLC 和细胞学确诊的 LM 患者的临床特征和治疗结果，这些患者在 LM 诊断后接受了第三代 EGFR-TKI 治疗。根据第三代EGFR-TKI的治疗剂量将患者分为高剂量组和标准剂量组。收集了LM的后续治疗方法，特别是不同剂量的第三代EGFR靶向药物的疗效。

结果

截至2023年8月27日截止日，中位随访期为28.7个月（范围0.6-40.2）。这105名接受第三代EGFR-TKI治疗的患者的临床缓解率（CRR）为54.3 % (57/105)，LM 诊断的中位总生存期 (OS) 为 12.3 个月（95% 置信区间 [CI] = 10.0–15.0）。其中，46例（43.8%）患者接受高剂量药物治疗，其余59例（56.2%）患者接受标准剂量药物治疗。与接受标准剂量治疗的患者相比，接受高剂量第三代 EGFR-TKIs 治疗的患者表现出更高的 CRR 和更长的 OS（65.2% vs. 45.8%，p = 0.047；15.0 vs. 10.2 个月，p = 0.014）。重要的是，高剂量第三代 EGFR-TKI 在所有亚组中均表现出优于标准剂量治疗的 OS（先前第一代/第二代 EGFR-TKI 耐药组，19.5 个月与 9.8 个月，p = 0.047；第三代 EGFR -TKI 耐药组，10.0 个月 vs. 4.3 个月，p = 0.045；EGFR-TKI 初治组，未达到 vs. 15.6 个月，p = 0.031)。多变量分析显示，高剂量第三代 EGFR-TKI、鞘内化疗、既往 TKI 治疗史和卡诺夫斯基体能状态评分是 OS 的独立预测因素（均 p < 0.05）。

结论

无论既往是否接触过 EGFR-TKI，高剂量第三代 EGFR-TKI 都是具有 EGFR 突变和 LM 的 NSCLC 患者的有效治疗方法。