Abstract
BACKGROUND: The C797S mutation is one of the most common mechanisms of acquired resistance to third generation EGFR TKIs, yet no approved therapies have been available to target it. Here we developed a novel selective EGFR C797S inhibitor, HS-10375, and report the results of pre-clinical research and the first-in-human phase 1 trial. METHODS: Ba/F3 cell lines and patient-derived cells expressing mutant EGFR were used to test the selectively inhibitory potency of HS-10375 in vitro, and cell line-derived xenograft animal models were used to evaluate the anticancer efficacy of HS-10375 in vivo. In the phase 1 trial, HS-10375 was administered orally at six dose levels (10-240 mg) daily (QD) in 21-day cycles, following a rule-based, rolling six design. The primary objectives were the safety, tolerability and maximum tolerated dose (MTD). The secondary objectives included PK parameters and anti-tumor activity. RESULTS: HS-10375 showed more potent activity in inhibiting EGFR phosphorylation compared to 1st to 3rd generation EGFR TKIs in C797S triple-mutant cell lines. HS-10375 also exhibited comparable inhibitory activity to 1st- and 2nd- generation EGFR TKIs and superior activity to 3rd-generation EGFR TKIs in C797S double-mutant cell lines. Furthermore, cells harboring EGFR double or triple C797S mutation underwent remarkable apoptosis upon HS-10375 treatment. HS-10375 effectively inhibited tumor growth in C797S triple-mutant mouse models. In the first-in-human trial, 28 patients with advanced or metastatic non-small cell lung cancers who harbored EGFR mutation and who had experienced treatment failure with EGFR TKI treatment received at least one dose of HS-10375. Dose-limiting toxicities were observed in 2 patients at 240 mg QD, and MTD was reached at HS-10375 150 mg QD. The most common treatment-related adverse events were vomit (37.0%), loss of appetite (33.3%), and elevated AST (33.3%). One patient with EGFR mutations showed tumor shrinkage after progression on five-line treatment including gefitinib, almonertinib, chemotherapy, immunotherapy, and EGFRxHER3 antibody-drug conjugate. CONCLUSIONS: HS-10375 demonstrated potent and mutant-selective activity against the EGFR C797S mutation in preclinical results, and showed an acceptable safety profile and objective response in a first-in-human phase 1 trial. Trial registration This trial is registered on China Drug Trials (CTR20220045), and ClinicalTrials.gov (NCT05435248).