Safety, Efficacy and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients with EGFR-mutated Advanced NSCLC: a Multicenter, Open-label, Phase I Trial.

Chih-Hsin Yang, James; Camidge, D Ross; Yang, Cheng-Ta; Zhou, Jianying; Guo, Renhua; Chiu, Chao-Hua; Chang, Gee-Chen; Shiah, Her-Shyong; Chen, Yuan; Wang, Chin-Chou; Berz, David; Su, Wu-Chou; Yang, Nong; Wang, Ziping; Fang, Jian; Chen, Jianhua; Nikolinakos, Petros; Lu, You; Pan, Hongming; Maniam, Ajit; Bazhenova, Lyudmila; Shirai, Keisuke; Jahanzeb, Mohammad; Willis, Maurice; Masood, Nehal; Chowhan, Naveed; Hsia, Te-Chun; Jian, Hong; Lu, Shun

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.