Limertinib在局部晚期或转移性EGFR T790M

SCI

20 June 2022

Efficacy and safety of Limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, singlearm, phase 2b study

( IF: JOT., 15.609)

• Shi Y, Li B, Wu L, Pan Y, Pan Z, Liu Y, Fan Y, Ji Y, Fang J, Shi Q, Shi J, Gao H, Hu Y, Wang X, He Z, Ma R, Zhang Y, Jiang D, Bai Y, Zhang Y, Huang L, Zhou T, Liu H, Wang D, Wen Q, Chen G, Zang A, Wang X, Zhang X, Hu J, Yang R, Zhang G, Gu K, Lin W, Qiming W, Wei Z, Zeng L, Lu H, Helong Z, Chen H, Song T. Efficacy and safety of Limertinib (ASK120067) in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer: a multicenter, single-arm, phase 2b study. J Thorac Oncol. 2022 Jun 1:S1556-0864(22)00267-2. 

• Correspondence:Yuankai Shi, MD Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing 100021, China. Tel: +86 10 87788293. Fax: +86 10 87788781. E-mail: syuankai@cicams.ac.cn.

Background 背景

Limertinib (ASK120067) is a newly developed third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both sensitizing EGFR and EGFR T790M mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer (NSCLC).

Limertinib（ASK120067）是一种新开发的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），针对EGFR和EGFR T790M同时突变的患者。本研究旨在评估Limertinib对局部晚期或转移性EGFR T790M突变非小细胞肺癌（NSCLC）患者的疗效和安全性。

Methods 方法

This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first or second-generation EGFR-TKIs or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160mg orally twice daily, until disease progression, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by Independent Review Committee (IRC) per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

这是一项在中国62家医院进行的单臂、开放标签、2b期研究。纳入了在第一代或第二代EGFR-TKIs后进展的或具有原发性EGFR T790M突变的局部晚期或转移性NSCLC患者，这些患者的肿瘤组织或血浆中有集中证实的EGFR-T790M突变。患者每天两次口服160mg Limertinib，直至疾病进展或出现不可接受的毒性。主要终点是独立审查委员会（IRC）根据实体瘤反应评估标准1.1中版的评估的客观反应率（ORR）。次要终点包括疾病控制率（DCR）、无进展生存期（PFS）、反应持续时间（DoR）、总生存期（OS）和安全性。根据美国国家癌症研究所不良事件通用术语标准4.03版评估安全性。

Results 结果

From June 24, 2019 to Feb 25, 2021, a total of 301 patients were enrolled and received the treatment of limertinib. All patients entered the full analysis set (FAS) and safety set (SS). By the data cutoff date on Sept 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range 0.3-26.3). Based on FAS, the IRC-assessed ORR was 68.8% (95% CI 63.2%-74.0%) and DCR was 92.4% (95% CI 88.8%-95.1%). The median PFS was 11.0 months (95%CI 9.7-12.4), median DoR was 11.1 months (95%CI 9.6-13.8), and median OS was not reached (NR) (95%CI 19.7 months-NR). Objective responses were achieved across all prespecified subgroups. For 99 (32.9%) patients with central nervous system (CNS) metastases, the ORR was 64.6% (95%CI 54.4%-74.0%), median PFS was 9.7 months (95%CI 5.9-11.6), and median DoR was 9.6 months (95%CI 8.1-15.2). For 41 patients who had evaluable CNS lesion, the confirmed CNS-ORR was 56.1% (95%CI 39.7%-71.5%) and median CNS-PFS was 10.6 months (95%CI 5.6-NE). In SS, 289 (96.0%) patients experienced at least one treatment related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%) and appetite decrease (28.2%). Grade ≥3 TRAEs occurred in 104 (34.6%) patients, with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%) and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred.

从2019年6月24日至2021年2月25日，共有301名患者入组并接受了Limertinib治疗。所有患者均进入完整分析集（FAS）和安全集（SS）。到2021年9月9日的数据截止日期为止，76人（25.2%）仍在接受治疗。中位随访时间为10.4个月（范围0.3-26.3）。基于FAS，IRC评估的ORR为68.8%（95% CI 63.2%-74.0%），DCR为92.4%（95% CI 88.8%-95.1%）。中位PFS为11.0个月（95% CI 9.7-12.4），中位DoR为11.1个月（95% CI 9.6-13.8），中位OS尚未达到（NR）（95% CI 19.7个月-NR）。所有预先指定的亚组均有客观反应。对于99例（32.9%）中枢神经系统（CNS）转移患者，ORR为64.6%（95% CI 54.4%-74.0%），中位PFS为9.7个月（95% CI 5.9-11.6），中位DoR为9.6个月（95% CI 8.1-15.2）。对于41名具有可评估CNS病变的患者，确诊的CNS-ORR为56.1%（95% CI 39.7%~71.5%），中位CNS-PFS为10.6个月（95% CI 5.6-NE）。在SS中，289名（96.0%）患者至少经历了一次治疗相关不良事件（TRAE），最常见的是腹泻（81.7%）、贫血（32.6%）、皮疹（29.9%）和食欲下降（28.2%）。104名（34.6%）患者发生≥3级的TRAE，最常见的包括腹泻（13.0%）、低钾血症（4.3%）、贫血（4.0%）和皮疹（3.3%）。导致剂量中断和剂量中断的TRAEs分别发生在24.6%和2%的患者中。未发生导致死亡的TRAE。

Conclusion 结论

Limertinib (ASK120067) demonstrated promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M mutated NSCLC. Clinical Trial information: NCT03502850.

Limertinib（ASK120067）在治疗局部晚期或转移性EGFR T790M突变NSCLC患者方面显示出良好的疗效和可接受的安全性。