2. Academic Validation
  3. Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial

  • J Thorac Oncol. 2020 Dec;15(12):1907-1918. doi: 10.1016/j.jtho.2020.09.001.
James Chih-Hsin Yang 1,  D Ross Camidge 2,  Cheng-Ta Yang 3,  Jianying Zhou 4,  Renhua Guo 5,  Chao-Hua Chiu 6,  Gee-Chen Chang 7,  Her-Shyong Shiah 8,  Yuan Chen 9,  Chin-Chou Wang 10,  David Berz 11,  Wu-Chou Su 12,  Nong Yang 13,  Ziping Wang 14,  Jian Fang 14,  Jianhua Chen 13,  Petros Nikolinakos 15,  You Lu 16,  Hongming Pan 17,  Ajit Maniam 18,  Lyudmila Bazhenova 19,  Keisuke Shirai 20,  Mohammad Jahanzeb 21,  Maurice Willis 22,  Nehal Masood 23,  Naveed Chowhan 24,  Te-Chun Hsia 25,  Hong Jian 26,  Shun Lu 26
Affiliations

Affiliations

  • 1 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China. Electronic address: chihyang@ntu.edu.tw.
  • 2 Department of Medicine Division of Medical Oncology, University of Colorado Health, Aurora, Colorado.
  • 3 Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, Republic of China.
  • 4 Department of Respiratory Medicine, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 5 Department of Medical Oncology, Jiangsu Province Hospital, Nanjing, Jiangsu, People's Republic of China.
  • 6 Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
  • 7 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China.
  • 8 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, Republic of China.
  • 9 Department of Oncology, Tongji Medical College of HUST, Wuhan, Hubei, China.
  • 10 Department of Occupational Medicine, Chang Gung Memorial Hospital- Kaohsiung, Kaohsiung, Taiwan, Republic of China.
  • 11 Department of Cellular Therapeutics, Beverly Hills Cancer Center, Beverly Hills, California.
  • 12 Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China.
  • 13 Department of Medical Oncology, Hunan Cancer Hospital, Changsha, Hunan, China.
  • 14 Department of Chest Medicine, Beijing Cancer Hospital, Beijing, China.
  • 15 Department of Research, University Cancer & Blood Center, LLC, Athens, Georgia.
  • 16 Department of Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
  • 17 Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 18 Division of Hematology and Oncology, Pacific Cancer Medical Center Inc., Anaheim, California.
  • 19 Department of Medicine, Moores Cancer Center, University of California San Diego Health, La Jolla, California.
  • 20 Department of Hematology and Oncology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
  • 21 Department of Clinical Medicine, Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida.
  • 22 Department of Oncology, University of Texas Medical Branch at Galveston, Galveston, Texas.
  • 23 Department of Medical Oncology, MultiCare Regional Cancer Center, MultiCare Institute for Research and Innovation, Tacoma, Washington.
  • 24 Department of Research, Baptist Healthcare Systems Inc., Baptist Health Floyd, New Albany, Indiana.
  • 25 Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan, Republic of China.
  • 26 Department of Oncology, Shanghai Chest Hospital, Shanghai, People's Republic of China.
PMID: 32916310 DOI: 10.1016/j.jtho.2020.09.001
Abstract

Introduction: Almonertinib (HS-10296) is a novel, third-generation EGFR 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 NSCLC that had progressed after pevious EGFR TKI therapy.

Methods: This phase 1, 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 the determination of EGFR T790M status. The safety, tolerability, antitumor 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 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 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% confidence interval [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 or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.

Keywords

EGFR T790M mutation; Epidermal growth factor receptor; non–small cell lung cancer; phase I trial; safety.

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