First-in-Human Phase 1 Study of ES-072, an Oral Mutant-Selective EGFR T790M Inhibitor, in Non–Small-Cell Lung Cancer
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 T max 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.
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In January 2018, ES-072 was registered for a phase I clinical trial (CTR20180074) to assess its efficacy in NSCLC patients with EGFR mutations.
“In January 2018, ES-072 was registered for a phase I clinical trial (CTR20180074) to assess its efficacy in NSCLC patients with EGFR mutations.182”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [182]
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- Authors
- Zheng, J., Shen, L., Jiang, N., Zhu, Y., Wu, L., Cao, H., Sun, W., Zhou, J., & Zhou, J.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Corresponding author
- Zhou, Jianya
- Venue
- Clinical Lung Cancer
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 21
- Issue
- 6
- Pages
- 509-519.e1
- ISSN
- 1525-7304 (ISSN-L)
- OpenAlex
- W3040766773
- Cited by
- 6
- References
- 31
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Lung Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Key Research and Development Program of Zhejiang Province (2019C03042)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- non-small cell lung cancer, third-generation EGFR-TKI, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, QT prolongation, anticancer activity, oral administration
- MeSH terms
- Administration, Oral, Aged, Amides, Carcinoma, Non-Small-Cell Lung, Female, Follow-Up Studies, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Piperazines, Prognosis, Maximum Tolerated Dose, Protein Kinase Inhibitors, Response Evaluation Criteria in Solid Tumors, ErbB Receptors
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