2. Academic Validation
  3. First-in-Human Phase 1 Study of ES-072, an Oral Mutant-Selective EGFR T790M Inhibitor, in Non-Small-Cell Lung Cancer

First-in-Human Phase 1 Study of ES-072, an Oral Mutant-Selective EGFR T790M Inhibitor, in Non-Small-Cell Lung Cancer

  • Clin Lung Cancer. 2020 Nov;21(6):509-519.e1. doi: 10.1016/j.cllc.2020.07.001.
Jing Zheng 1,  Lisha Shen 1,  Nan Jiang 1,  Yanping Zhu 1,  Lihua Wu 2,  He Cao 1,  Wenjia Sun 1,  Jianya Zhou 3,  Jianying Zhou 1
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
  • 2 Research Center of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
  • 3 Department of Respiratory Medicine, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: zhoujy@zju.edu.cn.
PMID: 32800640 DOI: 10.1016/j.cllc.2020.07.001
Abstract

Background: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are rapidly being developed for treatment of non-small-cell lung Cancer (NSCLC) in patients harboring EGFR T790M mutations. This first-in-human phase 1 study evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, tolerability, and pharmacokinetics (PK), and preliminarily determined the antitumor activity of ES-072 in NSCLC patients with EGFR T790M mutations.

Patients and methods: Dose escalation and expansion studies were performed using an accelerated titration method. Oral ES-072 doses (25-450 mg) were administrated once daily for single- and multiple-dose escalation trials. Characteristic PK parameters were assessed in the single-dose escalation phase and in the first cycle of the multiple-dose escalation phase. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to evaluate ES-072 antitumor activity.

Results: Nineteen patients were enrolled onto this study, 16 to the dose-escalation phase and 3 to the dose-expansion phase. The most common adverse events were QT interval prolongation (11/19, 57.9%), anemia (5/19, 26.3%), mouth ulceration (4/19, 21.1%), keratosis (4/19, 21.1%), and cough (4/19, 21.1%). Safety and tolerability evaluation of ES-072 showed an maximum tolerated dose of 300 mg, and the RP2D dose was therefore 300 mg once daily. PK analysis showed an ES-072 half-life of 24.5 hours and a Tmax of approximately 4 hours. The total objective response rate and disease control rate were 46.2% and 76.9%, respectively.

Conclusion: ES-072 was safe and well tolerated in NSCLC patients harboring EGFR T790M mutations, and adverse events were controllable and reversible. A RP2D of 300 mg once daily was determined, and preliminary investigations showed promising antitumor activity.

Keywords

ES-072; Epidermal growth factor receptor; Non–small-cell lung cancer; T790M; Tyrosine kinase inhibitor.

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