Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Medical Oncology and Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
JAMA Oncol. 2024 Oct 1;10(10):1342-1351. doi: 10.1001/jamaoncol.2024.2640.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
重要性：表皮生长因子受体（EGFR）-变体非小细胞肺癌（NSCLC）与中枢神经系统（CNS）转移的高发生率相关，即使在使用第一代或第二代 EGFR 酪氨酸激酶抑制剂（TKI）治疗后也是如此。
目的：研究第三代 EGFR TKI lazertinib 的 CNS 活性。
设计、地点和参与者：这是一项多中心、单臂、2 期非随机对照试验，在韩国进行，纳入了 EGFR 变体 NSCLC 患者，这些患者在第一代或第二代 EGFR TKI 治疗失败后出现无症状或轻度症状性脑转移。数据于 2021 年 6 月至 2022 年 4 月收集，数据截止日期为 2022 年 12 月 15 日。
暴露：lazertinib，240mg，每日一次。
主要终点和次要终点：主要终点是研究者评估的根据实体瘤反应评估标准 1.1 评估的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，以及总缓解率、缓解持续时间、颅内缓解持续时间、疾病控制率、总生存期、lazertinib 的脑脊液渗透率和安全性。
结果：在纳入的 40 名患者中，25 名（63%）为女性，中位（范围）年龄为 63（29-85）岁。共有 38 名患者可评估肿瘤反应，包括 12 名有软脑膜转移的患者。截止数据时，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%（21/38；95%CI，38.3-71.4）；T790M 阳性疾病患者为 80%（4/5；95%CI，28.4-99.5）；T790M 阴性疾病患者为 43%（9/21；95%CI，21.8-66.0）；T790M 未知疾病患者为 67%（8/12；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），T790M 阴性亚组为 15.4 个月（95%CI，7.9-未达到），T790M 未知亚组为 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。
结论：在这项研究中，lazertinib 在治疗失败后出现颅内转移的患者中具有显著的 CNS 活性，无论 T790M 状态如何，包括伴有或不伴有软脑膜转移的患者。这些结果表明，在先前接受过 EGFR TKI 治疗后 CNS 转移进展的 EGFR 变体 NSCLC 患者中，使用 lazertinib 替代脑部局部治疗可能是一种潜在策略。
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