SCI
22 August 2024
Lazertinib in EGFR-Variant Non–Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors
A Nonrandomized Controlled Trial
（IF: JAMA Oncology, 22.5）
Hong MH, Choi YJ, Ahn HK, Lim SM, Keam B, Kim DW, Kim TM, Youk J, Kim YJ, Hwang S, Kim S, Kim JW, Kim HR, Kang JH. Lazertinib in EGFR-Variant Non-Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors: A Nonrandomized Controlled Trial. JAMA Oncol. 2024 Aug 15:e242640.
Corresponding Authors: Hye Ryun Kim, MD, PhD, Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea (nobelg@yuhs.ac); Jin Hyoung Kang, MD, PhD, Division of Medical Oncology, Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, Republic of Korea (oncologykang@naver.com).
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).
EGFR变异型非小细胞肺癌（NSCLC）与较高的中枢神经系统（CNS）转移率相关，即使采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（TKIs）进行治疗时也是如此。
To investigate CNS activity with lazertinib, a third-generation EGFR TKI.
为了研究lazertinib，一种第三代EGFR TKI，在中枢神经系统（CNS）中的活性。
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.
这项多中心、单臂、2期非随机对照试验在韩国进行，纳入了第一代或第二代EGFR TKI治疗失败后出现无症状或轻度症状脑转移的EGFR变异型NSCLC患者。数据收集于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, once daily.
Lazertinib，240毫克，每天一次。
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.
主要终点是研究者根据实体肿瘤疗效评价标准1.1版，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，以及总体ORR、响应持续时间、颅内响应持续时间、疾病控制率、总生存期、lazertinib的脑脊液渗透和安全性。
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.
在40名纳入的患者中，25名（63%）为女性，中位（范围）年龄为63岁（29-85岁）。共有38名患者可评估肿瘤响应，包括12名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个月（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，iORR为80%（5人中的4人；95% CI，28.4-99.5）；对于T790M阴性疾病的患者，iORR为43%（21人中的9人；95% CI，21.8-66.0）；对于T790M未知疾病的患者，iORR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），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在脑脊液中的渗透率为46.2%（95% CI，10.0-49.6），进一步支持了其颅内响应的机制。大多数不良事件为1级或2级。
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.
在本研究中，无论T790M状态如何，lazertinib对转移性EGFR 变异型NSCLC患者，在第一代或第二代EGFR TKI治疗失败后，无论是否伴有软脑膜转移，均具有显著的中枢神经活性，可抑制颅内转移进展。这些结果表明，在先前接受过EGFR TKI治疗的EGFR变异型NSCLC患者出现脑转移后，使用lazertinib代替脑部局部治疗可能是一个潜在的策略。
