HS-10296 – A Novel Third Generation EGFR Tyrosine Kinase Inhibitor: Results of the First-in-Human Phase 1 Trial in Patients with Previously Treated EGFR Mutant Advanced Non-Small-Cell Lung Cancer

Abstract

Background: HS-10296 is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against both EGFR-sensitizing and T790M-resistant mutations. This first-in-human trial aimed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of HS-10296 in EGFR inhibitor-resistant non-small-cell lung cancer (NSCLC) patients. Methods: This open-label phase 1 trial included dose-escalation and dose-expansion phases. Patients >18 years with locally advanced/metastatic EGFR mutant NSCLC that progressed after 1st/2nd EGFR-TKI were eligible. Confirmation of EGFR T790M-positive mutation was required for the dose-expansion cohort. During dose escalation, HS-10296 was administered orally at 55 to 260 mg once-daily following a rolling six design. During dose-expansion, patients (30 patients/dose level) received the recommended dose once-daily in 21-day cycles. The primary endpoint was safety and tolerability. Pharmacokinetics and anti-tumor activity of HS-10296 were also assessed. Findings: Between May 2017 and September 2018, a total of 120 patients were enrolled: 26 patients in the dose-escalation cohort and 94 in the expansion cohort. No dose-limiting toxicity occurred in the dose-escalation phase, but no dose expansion was opened for 260-mg because of plateauing of drug exposures. The most common drug-related AEs were increased blood creatine phosphokinase (20%), diarrhea (16.7%), cough (16.7%), and rash (15.8%). The most common drug-related grade ≥3 adverse events were increased blood creatine phosphokinase (10.0%) and increased alanine aminotransferase (3.3%). When considering all patients, no patient had a complete response, 60 (50.0%) had partial response, and 47 (39.2%) had stable disease. The objective response rate and disease control rate were 50.0% (95%CI: 40.7%-59.3%) and 89.2% (95%CI: 82.2%-94.1%) respectively. Median progression-free survival was 9.6 (95%CI: 8.3-11.1) months. Interpretation: HS-10296 is safe, tolerable, and effective in patients with T790M-positive EGFR mutant, locally advanced/metastatic NSCLC who progressed after EGFR-TKI. Trial Registration: This trial is registered with ClinicalTrials.gov, NCT02981108. Funding Statement: This study was funded by the Hansoh Pharmaceutical Group Co. Ltd. Declaration of Interests: All authors declare that they have no competing interests. Ethics Approval Statement: The study was conducted according to the principles of the Declaration of Helsinki and the guidelines of the Good Clinical Practice of the International Council for Harmonisation (ICH). The study protocol was approved by the ethics committees of each participating center. Written informed consent was obtained from all subjects before enrollment.