SH-1028是一种新型第三代EGFR酪氨酸激酶抑制剂（TKI），可使EGFR T790M突变的NSCLC患者受益。在此，作者首次报道了其临床安全性、初步疗效和药代动力学（PK）特征。符合条件的患者为EGFR T790M突变、局部晚期非小细胞肺癌（NSCLC）或转移性NSCLC患者，已接受先前的EGFR TKI治疗但疾病进展。患者每天口服SH-1028五种剂量水平（60毫克、100毫克、200毫克、300毫克和400毫克），直到疾病进展、不能耐受的毒性反应或患者退出。主要终点是安全性、剂量限制毒性（DLT）、最大耐受剂量（MTD）和PK特征。次要终点包括客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）等。结果：在2020年12月31日数据截止时，共有20名患者参加了试验，300毫克组中的三名患者中有两名经历了DLT，而240毫克组中没有观察到DLT，240毫克被确定为SH-1028的MTD。95.0%（20名患者中的19名）报告了治疗相关的不良事件（TRAEs），严重不良事件的发生率为20.0%（20人中的4人）。200毫克组的ORR和DCR分别为75.0%（95%置信区间[CI]，19.41-99.37）和75.0%（95% CI，19.41-99.37）；总体ORR为40.0%（95% CI，19.12-63.95），DCR为70.0%（95% CI，45.72-88.11）。根据PK特征，未来研究的剂量方案为每日一次200毫克。SH-1028在每天口服200毫克的EGFR T790M突变患者中表现出可控制的安全性和有希望的抗肿瘤活性。肺癌具有较高的发病率和死亡率，在2020年估计有180万人死于肺癌。非小细胞肺癌约占肺癌的85%。第一代或第二代EGFR TKI的微弱选择性常常导致治疗相关的不良事件，如间质性肺病、皮疹、腹泻等，以及在大约1年内获得的药物抵抗力。每日一次200毫克的SH-1028剂量表现出了可控制的安全性和有希望的抗肿瘤活性。© 2023该文章作者。《癌症》由Wiley Periodicals LLC代表美国癌症学会出版。

SH-1028 is a new third-generation EGFR tyrosine kinase inhibitors (TKI) to benefit patients with EGFR T790M-mutated NSCLC. Here, the authors report its clinical safety, preliminary efficacy, and pharmacokinetic (PK) profile for the first time.Patients with EGFR T790M mutation, locally advanced non-small cell lung cancer (NSCLC), or metastatic NSCLC who had progressed after previous EGFR TKI therapy were eligible. Patients received SH-1028 at five oral dose levels (60 mg, 100 mg, 200 mg, 300 mg, and 400 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were the safety, dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and PK profile. Secondary end points included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), etc. RESULTS: Data cut off on December 31, 2020, a total of 20 patients were enrolled during the trial, two of three patients in 300 mg cohort experienced a DLT, and no DLT was observed in 240 mg cohort, 240 mg was determined to be the MTD of SH-1028. A total of 95.0% (19 of 20) of patients reported treatment-related adverse events (TRAEs), and the incidence of serious adverse events was 20.0% (4 of 20). The ORR and DCR of the 200 mg cohort were 75% (95% confidence interval [CI], 19.41-99.37) and 75.0% (95% CI, 19.41-99.37), respectively. The overall ORR was 40% (95% CI, 19.12-63.95), and DCR was 70.0% (95% CI, 45.72-88.11). According to the PK profile, the dosage regimen for future studies was determined as 200 mg once daily.SH-1028 showed a manageable safety and promising antitumor activity in patients with EGFR T790M mutation at the dose of 200 mg once daily.Lung cancer has a high morbidity and mortality, with an estimated 1.8 million deaths in 2020. Non-small cell lung cancer accounts for approximately 85% of lung cancer. First- or second-generation EGFR TKIs' weak selectivity often led to the occurrence of treatment-related adverse events, such as interstitial lung disease, rash, diarrhea, etc., along with acquired drug resistance within approximately 1 year. A dose of 200 mg of SH-1028 once daily showed a preliminary antitumor activity with manageable safety in patients with EGFR T790M mutation.© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.