First-in-Human Phase I 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-tyrosine kinase inhibitors (EGFR-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 I study evaluated the maximum tolerated dose (MTD), recommended Phase II dose (RP2D), safety, tolerability, pharmacokinetics (PK), and preliminarily determined the antitumor activity of ES-072 in NSCLC patients with EGFR-T790M mutations. 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) to evaluate ES-072 antitumor activity. Results Nineteen patients were enrolled in this study, 16 to the dose-escalation phase and 3 to the dose-expansion phase. The most common adverse events (AE) were Q-T 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 MTD of 300 mg, and the RP2D dose was therefore 300 mg QD. PK analysis showed an ES-072 half-life of 24.5 h and a Tmax of approximately 4 h. The total objective response rate and disease control rate were 46.2 % and 76.9 %, respectively. Conclusions ES-072 was safe and well tolerated in NSCLC patients harboring EGFR-T790M mutations, and AEs were controllable and reversible. A RP2D of 300 mg QD was determined and preliminary investigations showed promising antitumor activity.