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

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.

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