Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre
Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre
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DOI：
10.1016/s2213-2600(20)30455-0
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发表时间：
2021-08-03
影响因子：
76.2
通讯作者：
Gu, Chuan
中科院分区：
文献类型：
--
作者：
Shi, Yuankai;Hu, Xingsheng;Gu, Chuan
Furmonertinib（AST 2818）是第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），靶向EGFR和EGFR Thr790Met（T790M）突变。本研究旨在评估呋莫替尼在EGFR T790 M突变的晚期非小细胞肺癌（NSCLC）患者中的疗效和安全性。方法本研究是一项在中国大陆46家医院进行的单臂、开放标签、2b期研究。在第一代或第二代EGFR TKI治疗后进展的肿瘤组织中存在中心确认的EGFR T790 M突变或原发性EGFR T790 M突变的局部晚期或转移性NSCLC患者接受furmonertinib 80 mg口服每日一次治疗。主要终点为客观缓解率。根据实体瘤疗效评价标准（第1.1版），通过设盲独立中心审查，在所有基线时有可测量疾病并接受至少一剂furmonertinib的患者中评估疗效。根据不良事件通用术语标准（第4.03版），在随访期间接受至少一剂furmonertinib且至少有一次安全性评估的所有患者中评估安全性。本研究已在ClinicalTrials注册。gov（NCT 03452592），并正在进行生存随访。结果从2018年6月4日至2018年12月8日，220例患者接受了furmonertinib治疗。所有220例患者均纳入疗效和安全性分析。在2020年1月29日的数据截止点，71名（32%）患者仍在接受治疗。中位随访持续时间为9个月至6个月（范围为7个月至19个月）。客观缓解率为74%（163/220 [95%CI 68 - 80]）。58例（26%）患者发生3级或以上不良事件，25例（11%）患者发生治疗相关3级或以上不良事件。最常见的全因3级或3级以上不良事件为γ-谷氨酰转移酶升高（5例; 2%）、天冬氨酸转氨酶升高、丙氨酸转氨酶升高、低钠血症、高血压、肺部感染、高镁血症和心包积液（各3例; 1%）。10例（5%）患者报告了治疗相关腹泻，16例（7%）患者报告了皮疹，均为1 - 2级。52例（24%）患者报告了严重不良事件，其中12例（5%）经研究者评估可能与治疗相关。Furmonertinib治疗EGFR T790 M突变NSCLC患者的疗效和安全性可接受。预计Furmonertinib将成为中国人群中第一代或第二代EGFR TKI之后的新治疗选择。由上海艾立特医药科技有限公司、中华人民共和国科学技术部、中国医学科学院资助。版权所有（c）2021.爱思唯尔有限公司版权所有。
Background Furmonertinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both sensitising EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to assess the efficacy and safety of furmonertinib in patients with EGFR T790M mutated advanced non-small-cell lung cancer (NSCLC). Methods This study was a single-arm, open-label, phase 2b study at 46 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumour tissue who progressed after first or second generation EGFR TKIs or with primary EGFR T790M mutations received furmonertinib 80 mg orally once daily. The primary endpoint was objective response rate. Efficacy was assessed by blinded independent central review as per the Response Evaluation Criteria in Solid Tumors (version 1.1) in all patients who had measurable disease at baseline and received at least one dose of furmonertinib. Safety was assessed as per the Common Terminology Criteria for Adverse Events (version 4.03) in all patients who received at least one dose of furmonertinib with at least one safety assessment during follow-up. This study is registered with ClinicalTrials. gov (NCT03452592) and is ongoing for survival follow-up. Findings From Jun 4, 2018, to Dec 8, 2018, 220 patients received furmonertinib treatment. All 220 patients were included in the efficacy and safety analyses. At the data cutoff point of Jan 29, 2020, 71 (32%) patients remained on treatment. The median duration of follow-up was 9middot6 months (range 0middot7-19middot4). The objective response rate was 74% (163 of 220 [95% CI 68-80]). Grade 3 or higher adverse events occurred in 58 (26%) patients and treatment related grade 3 or higher adverse events occurred in 25 (11%) patients. The most common all-cause grade 3 or higher adverse events were increased gamma-glutamyltransferase (five; 2%), increased aspartate aminotransferase, increased alanine aminotransferase, hyponatraemia, hypertension, pulmonary infection, hypermagnesaemia, and pericardial effusion (three each; 1%). Treatment-related diarrhoea was reported in ten (5%) patients and rashes were reported in 16 (7%) patients, all grade 1-2. Serious adverse events were reported in 52 (24%) patients, of which 12 (5%) were possibly treatment-related as evaluated by the investigator. Interpretation Furmonertinib has promising efficacy and an acceptable safety profile for the treatment of patients with EGFR T790M mutated NSCLC. Furmonertinib is expected to become a new treatment option after first or second generation EGFR TKIs in the Chinese population. Funding Shanghai Allist Pharmaceutical Technology, Ministry of Science and Technology of the People's Republic of China, and Chinese Academy of Medical Sciences. Copyright (c) 2021. Elsevier Ltd. All rights reserved.