INTRODUCTION Almonertinib (HS-10296) is a novel, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer (NSCLC) that had progressed after prior EGFR-TKI therapy. METHODS This phase I, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220 and 260 mg) and dose-expansion cohorts (55, 110 and 220 mg) with once-daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for determination of EGFR T790M status. The safety, tolerability, anti-tumor activity and pharmacokinetics of almonertinib were evaluated. RESULTS A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mgregimen was not further evaluated in the dose-expansion phase due to safety concerns and saturation of exposure. The most common treatment-related grade ≥3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95%CI: 42-63) and 92% (95%CI: 84∼96), respectively. Median progression∼free survival was 11.0 months (95%CI: 9.5∼not reached) months. CONCLUSIONS Almonertinib is safe, tolerable and effective for patients with locally advanced/metastatic NSCLC harboring the EGFR T790M mutation who were pre-treated with EGFR-TKIs.

中文翻译：

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Almonertinib (HS-10296) 在 EGFR 突变晚期 NSCLC 预处理患者中的安全性、有效性和药代动力学：一项多中心、开放标签、I 期试验

简介 Almonertinib (HS-10296) 是一种新型的第三代表皮生长因子受体酪氨酸激酶抑制剂 (EGFR-TKI)，针对 EGFR 致敏突变和 T790M 耐药突变。这项首次人体试验旨在评估阿莫替尼在既往 EGFR-TKI 治疗后进展的局部晚期或转移性 EGFR 突变阳性非小细胞肺癌 (NSCLC) 患者中的安全性、有效性和药代动力学。方法 该 I 期、开放标签、多中心临床试验 (NCT0298110) 包括剂量递增（55、110、220 和 260 毫克）和剂量扩展队列（55、110 和 220 毫克），每天一次口服阿莫替尼. 在每个扩展队列中，获得肿瘤活检以测定 EGFR T790M 状态。安全性、耐受性、评估了阿莫替尼的抗肿瘤活性和药代动力学。结果 共招募了 120 名患者（剂量递增队列中的 26 名患者和剂量扩展队列中的 94 名患者）。在剂量递增阶段未定义最大耐受剂量；由于安全问题和暴露饱和，在剂量扩展阶段没有进一步评估 260 mgregimen。最常见的治疗相关≥3 级不良事件是血肌酸磷酸激酶升高 (10%) 和丙氨酸转氨酶升高 (3%)。在剂量扩展队列中的 94 例 EGFR T790M 突变患者中，研究者评估的客观缓解率和疾病控制率分别为 52%（95%CI：42-63）和 92%（95%CI：84-96） ， 分别。中位进展∼无生存期为 11.0 个月（95% CI：9.5∼未达到）个月。