Abstract CT302: The safety, tolerability, and efficacy of HS-10504 in patients with EGFR mutation-positive locally advanced or metastatic NSCLC: Initial results from a first-in-human phase 1 study

Abstract Background: The EGFR C797S mutation is a major resistance mechanism following third-generation EGFR tyrosine kinase inhibitors (TKIs) treatment in EGFR-mutant NSCLC, with no clinically validated and accessible target therapies. HS-10504 is a novel, potent, and highly selective fourth-generation EGFR TKI designed to target tumors with EGFR sensitizing mutations and C797S with or without T790M. Here we report the initial results of HS-10504 from a first-in-human phase 1 study. Methods: This single-arm, open-label, multicenter phase 1 study (NCT06461156; 26 centers in China) enrolled patients (pts) with locally advanced/metastatic NSCLC harboring EGFR sensitizing mutations, who failed prior EGFR TKI treatment. The escalation phase evaluated oral doses from 50 mg to 500 mg once daily (QD). The study's primary objectives were to evaluate safety, tolerability, and preliminary efficacy. Results: As of December 25, 2025, 82 pts had been enrolled and dosed. No dose-limiting toxicities were observed during the dose-escalation phase (n=20), and the maximum tolerated dose was not reached at doses up to 500 mg QD. In the dose expansion phase, 300 mg and 400 mg QD were further investigated, and 400 mg showed more promising clinical benefit. Among pts treated at the 400 mg QD dose level (n=35), selected as the recommended phase 2 dose (RP2D), all pts had stage IV adenocarcinoma with EGFR C797S mutation (median age 61 years, range: 35-78; 71.4% female). Twenty-five pts (71.4%) had received ≥2 prior lines of anti-tumor therapy, and all pts had previously received at least one third-generation EGFR TKI. Overall, HS-10504 demonstrated a favorable and manageable safety profile, with most treatment-emergent adverse events (TEAEs) being Grade 1-2. Grade ≥3 TEAEs occurred in 74.3% (26/35) of patients and were primarily laboratory abnormalities, including decreased lymphocyte count (31.4%) and anemia (14.3%), which were clinically manageable. TEAEs leading to permanent treatment discontinuation occurred in 2.9% (1/35), with no fatal TEAEs reported. At the RP2D of 400 mg QD (n=34, efficacy-evaluable set), encouraging antitumor activity was observed. The partial response was observed in 17 (50%) pts and stable disease in 14 (41.2%) pts. The confirmed objective response rate was 47.1% (95% CI: 29.8-64.9), and the disease control rate was 91.2% (95% CI: 76.3-98.1). Most pts remained on treatment as of the data cut-off date. Conclusions: HS-10504 demonstrated a manageable safety profile and encouraging antitumor activity in patients with advanced cancer harboring EGFR C797S resistance mutations, supporting further development of HS-10504 at the selected RP2D and its continued evaluation as a potential oral targeted therapy for EGFR C797S mutation-mediated resistance. Citation Format: Zhanhong Xie, Qiming Wang, Lin Wu, Jun Ge, Jianchun Duan, Juan Li, Yalei Zhang, Yan Yu, Jian Fang, Peng Chen, Zhangzhou Huang, Wei Zheng, Qing Bi, Haibo Zhang, Wenfeng Li, Ai Wang, Lu Chen, Xiaoqing Zhang, Jianxing He. The safety, tolerability, and efficacy of HS-10504 in patients with EGFR mutation-positive locally advanced or metastatic NSCLC: Initial results from a first-in-human phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT302.