ImportanceEGFR-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).ObjectiveTo investigate CNS activity with lazertinib, a third-generation EGFR TKI.Design, Setting, and ParticipantsThis 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.ExposureLazertinib, 240 mg, once daily.Main Outcomes and MeasuresThe 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.ResultsAmong 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.Conclusions and RelevanceIn 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.Trial RegistrationClinicalTrials.gov Identifier: NCT05326425

中文翻译：

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Lazertinib 治疗既往 EGFR 酪氨酸激酶抑制剂治疗 CNS 失败的 EGFR 变体非小细胞肺癌


重要性EGFR 变异型非小细胞肺癌 （NSCLC） 与中枢神经系统 （CNS） 转移率高相关，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） 治疗也是如此。目的研究第三代 EGFR TKI.Design lazertinib 的 CNS 活性、环境和参与者这项多中心单臂 2 期非随机对照试验在韩国进行，包括第一代或第二代 EGFR TKI 治疗失败后无症状或轻度症状脑转移的 EGFR 变异型 NSCLC 患者。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。主要结局和措施主要终点是根据研究人员评估的实体瘤反应评估标准 1.1 版，可评估人群的颅内客观缓解率 （iORR）。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 ORR、反应持续时间、颅内反应持续时间、疾病控制率、总生存期、lazertinib 的脑脊液渗透性和安全性。结果在 40 例纳入的患者中，25 例 （63%） 为女性，中位 （范围） 年龄为 63 （29-85） 岁。共有 38 例患者可评估肿瘤反应，包括 12 例软脑膜转移患者。在数据截止时，中位 （范围） 随访为 13.6 （2.9-17.7） 个月。可评估人群的 iORR 为 55%（38 人中有 21 人;95% CI，38.3-71.4）;对于 T790M 阳性疾病患者，80% （5 中的 4;95% CI，28.4-99.5);对于 T790M 阴性疾病患者，为 43% （21 例中的 9 例;95% CI，21.8-66.0）;对于 T790M 未知疾病患者，为 67% （12 例中有 8 例;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 - 未达标），T790M 阴性亚组为 15.4 个月 （95% CI，7.9 - 未达标），T790M 未知亚组为 18.0 个月 （95% CI，3.9 - 未达标）。lazertinib 的脑脊液渗透率为 46.2% （95% CI，10.0-49.6），进一步支持其颅内反应机制。结论和相关性在这项研究中，无论 T790M 状态如何，lazertinib 在转移性 EGFR 变异型 NSCLC 患者中接受第一代或第二代 EGFR TKIs 治疗失败后，对颅内转移进展伴或不伴软脑膜转移具有显着的 CNS 活性。这些结果表明，对于既往 EGFR TKI 治疗后 CNS 转移进展的 EGFR 变异型 NSCLC 患者，使用拉泽替尼代替脑局部治疗可能是一种潜在策略。试验注册临床试验。gov 标识符： NCT05326425