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Clinical Trial
. 2025 Jun 4;23(1):628.
doi: 10.1186/s12967-025-06613-0.

HS-10375, a selective EGFR C797S tyrosine kinase inhibitor, in advanced non-small cell lung cancer

Jianhua Zhan #  1 , Jinhui Xue #  1 , Lin Wu #  2 , Zhiye Zhang #  3 , Qiming Wang #  4   5 , Yuxiang Ma  1 , Yan Huang  1 , Yunpeng Yang  1 , Yuanyuan Zhao  1 , Wenfeng Fang  1 , Yang Zhang  1 , Qianwen Liu  1 , Wen Xu  6 , Yan Yang  6 , Zhenming Chen  6 , Baili Song  6 , Danni Sun  6 , Xia Sun  6 , Peng Gao  6 , Hongyun Zhao  7 , Li Zhang  8
Affiliations
Clinical Trial

HS-10375, a selective EGFR C797S tyrosine kinase inhibitor, in advanced non-small cell lung cancer

Jianhua Zhan et al. J Transl Med. .

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).

Keywords: C797S mutation; EGFR TKI; HS-10375; Non-small cell lung cancer; Targeted therapy.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This clinical trial was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (A2021-184–01). Informed consent was provided by all recruited subjects prior to the study. Consent for publication: Written informed consent for publication of individual data was obtained from all patients. Competing interests: W.X., Yan Yang, Z.C., B.S., D.S., X.S. and P.G. are the employees of Hansoh Pharmaceutical Group Co. Ltd., Shanghai, China. Other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The inhibitory activity of HS-10375 against EGFR C797S in vitro. A The chemical structure of HS-10375 and its interaction model binding to EGFR L858R/T790M/C797S. B, C The kinase inhibitory activity of HS-10375 against EGFR WT and EGFR C797S (Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S), as well as other EGFR mutations (Del19, T790M, L858R, L858R/T790M, and Del19/T790M). D Mean IC50 values for HS-10375 and TQB3804 in different EGFR mutations. All values are the average of two or three independent biological replicates. E The anti-proliferation activity of HS-10375 in A431 and Ba/F3 Del19/T790M/C797S cells. F The inhibitory activity of HS-10375 against other tyrosine kinases
Fig. 2
Fig. 2
The effects of HS-10375 on EGFR phosphorylation in vitro. A The cellular p-EGFR inhibition activity of HS-10375 and other EGFR TKIs. B–G Representative western blots comparing inhibition of EGFR-mediated signaling in Ba/F3 cells with different EGFR mutants by erlotinib, afatinib, osimertinib, and HS-10375. OR: osimertinib resistance. H Flow cytometry analysis of HS-10375 and osimertinib-induced apoptosis percentage in BaF3 EGFR-L858R/C797S, Ba/F3 EGFR-Del19/T790M/C797S, and PC9 EGFR-Del19/T790M/C797S cells
Fig. 3
Fig. 3
The antitumor activity of HS-10375 against EGFR-mutant models in vivo. A Antitumor activity of HS-10375 and TQB3804 in PC9 EGFR-Del19/T790M/C797S xenograft model. B, C Antitumor activity of HS-10375 in Ba/F3 EGFR-Del19/T790M/C797S and Ba/F3 EGFR-L858R/T790M/C797S xenograft models. D Antitumor activity of HS-10375 in the PDX model LD1–0025–200717 (EGFR Del19/T790M/C797S). Tumor volume at the endpoint versus vehicle control was performed by two-way ANOVA (**, P < 0.01; ***, P < 0.001). E Plasma, tumor and brain concentration profiles of HS-10375 in the Ba/F3 EGFR-Del19/T790M/C797S xenograft model after single oral administration. F PK parameters of HS-10375 in the Ba/F3 EGFR-Del19/T790M/C797S xenograft model. G Western blot analysis of p-EGFR, p-ERK, and total ERK in the Ba/F3 EGFR-Del19/T790M/C797S xenograft tumors in mice that were dosed with 20 mg/kg of HS-10375
Fig. 4
Fig. 4
Study flowchart
Fig. 5
Fig. 5
Response to HS-10375 in the patient with C797S mutation during the phase 1 study. Serial CT images at baseline and week 6 revealed significant improvements in the target lesion of the inferior lobe of the right lung
See this image and copyright information in PMC

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