即使使用第一代或第二代表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗，EGFR 变异型非小细胞肺癌 (NSCLC) 仍与中枢神经系统 (CNS) 转移率较高相关). 调查第三代 EGFR TKI 拉泽替尼 (lazertinib) 的中枢神经系统活性。 这项多中心单臂、2 期非随机对照试验在韩国进行，纳入了 EGFR 变异 NSCLC 患者，这些患者在治疗失败后出现无症状或轻度症状脑转移使用第一代或第二代 EGFR TKI 治疗。数据收集时间为2021年6月至2022年4月，数据截止日期为2022年12月15日。Lazertinib，240 mg，每日一次。主要终点是根据疗效评估在可评估人群中的颅内客观缓解率（iORR）实体瘤标准 1.1 版由研究者评估。次要终点包括 T790M 阴性疾病和孤立性 CNS 进展患者的颅内无进展生存期 (iPFS) 和 iORR，以及总体 ORR、缓解持续时间、颅内缓解持续时间、疾病控制率、总体生存、脑脊液渗透率在 40 名纳入的患者中，25 名 (63%) 是女性，中位年龄 (范围) 为 63 (29-85) 岁。共有 38 名患者进行了肿瘤反应评估，其中包括 12 名患有软脑膜转移的患者。在数据截止时，中位（范围）随访时间为 13.6（2.9-17.7）个月。可评估人群的 iORR 为 55%（38 人中的 21 人；95% CI，38.3-71.4）；对于 T790M 阳性疾病的患者，80%（5 中的 4；95% CI，28.4-99.5）；对于 T790M 阴性疾病患者，43%（21 人中的 9 人；95% CI，21.8-66.0）；对于 T790M 未知疾病的患者，该比例为 67%（12 人中的 8 人；95% CI，34.9-90.1）。可评估人群的中位 iPFS 为 15.8 个月（95% CI，15.2-未达到），T790M 阳性亚组为 15.2 个月（95% CI，4.2-未达到），15.4 个月（95% CI，7.9-未达到） T790M 阴性亚组为 18.0 个月（95% CI，3.9-未达到）。 Lazertinib的脑脊液渗透率为46.2%（95% CI，10.0-49.6），为其颅内反应机制提供了进一步支持。大多数不良事件为 1 级或 2 级。在这项研究中，无论 T790M 状态如何，Lazertinib 对第一代或第二代 EGFR TKI 治疗失败后的颅内转移（伴或不伴软脑膜转移）的进展具有显着的 CNS 活性。患有转移性 EGFR 变异 NSCLC。这些结果表明，对于既往 EGFR TKI 治疗后 CNS 转移进展的 EGFR 变异 NSCLC 患者，使用 Lazertinib 代替脑局部治疗可能是一种潜在策略。ClinicalTrials.gov 标识符：NCT05326425。

EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).To investigate CNS activity with lazertinib, a third-generation EGFR TKI.This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022.Lazertinib, 240 mg, once daily.The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety.Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2.In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment.ClinicalTrials.gov Identifier: NCT05326425.