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<p>Claudin-18 isoform 2 (CLDN18.2), a tight junction protein expressed in non-malignant gastric epithelium and exposed on tumor cell surface during malignant transformation, is a promising therapeutic target for gastric and gastroesophageal junction (G/GEJ) cancers. SHR-A1904 is an antibody–drug conjugate comprising CLDN18.2-targeting monoclonal antibody, a DNA topoisomerase I inhibitor payload and a cleavable peptide-based linker. We conducted a first-in-human, three-stage, phase 1 study to evaluate SHR-A1904 in 95 previously treated patients with CLDN18.2-positive advanced G/GEJ cancer. In the dose-escalation stage (0.6–8.0 mg kg<sup>−1</sup>), dose-limiting toxicities were observed in two patients at 4.8 mg kg<sup>−1</sup> (grade 3 febrile neutropenia and grade 3 increased blood bilirubin) and in one patient at 6.0 mg kg<sup>−1</sup> (grade 3 gastric mucosal lesion). The maximum tolerated dose was not reached, and 6.0 mg kg<sup>−1</sup> and 8.0 mg kg<sup>−1</sup> were selected for pharmacokinetic and efficacy expansion. Treatment-emergent adverse events occurred in all 95 patients, most commonly anemia (72 (75.8%)), nausea (64 (67.4%)), hypoalbuminemia (61 (64.2%)) and decreased white blood cell count (56 (58.9%)). Additionally, 59 patients (62.1%) experienced drug-related grade 3 or higher adverse events. No treatment-related deaths were reported. Among response-evaluable patients, the confirmed objective response rate was 24.2% (95% confidence interval (CI), 11.1–42.3) at 6.0 mg kg<sup>−1</sup> and 25.0% (95% CI, 12.1–42.2) at 8.0 mg kg<sup>−1</sup>. The median progression-free survival was 5.6 months (95% CI, 3.0–6.9) at 6.0 mg kg<sup>−1</sup> and 5.8 months (95% CI, 3.0–8.6) at 8.0 mg kg<sup>−1</sup>. In conclusion, SHR-A1904 demonstrated a manageable safety profile and encouraging anti-tumor activity in patients with CLDN18.2-positive G/GEJ cancer, warranting further investigation. ClinicalTrials.gov identifier: <a href="https://clinicaltrials.gov/study/NCT04877717">NCT04877717</a>.</p>

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The antibody–drug conjugate SHR-A1904 for targeting CLDN18.2 in advanced gastric or gastroesophageal junction cancer: a phase 1 trial

  • 期刊论文

  • 发表日期：

    2025年7月16日

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  • Dan-Yun Ruan,
  • Hao-Xiang Wu,
  • Su-Xia Luo,
  • Wen-Wen Huang,
  • Xin-Jun Liang,
  • Zuo-Xing Niu,
  • Qi Dang,
  • Hong-Li Li,
  • Zhan-Yu Pan,
  • Hong-Xia Lu,
  • Yan-Qiao Zhang,
  • Xing-Ya Li,
  • Xiu-Ying Xiao,
  • Shi-Rong Cai,
  • Yu-Gang Dong,
  • Jian Zhang,
  • Zhou Li,
  • Hai-Tao Lan,
  • Xin Wang,
  • Ying Zhou,
  • Lian Liu,
  • He-Li Liu,
  • Ping-Sheng Xu,
  • Ai-Li Suo,
  • Rui-Nuo Jia,
  • Yong-Qiang Li,
  • Xiao-Dong Peng,
  • Si-Chen Wang,
  • Ai-Ai Yu,
  • Jie Xie,
  • Miao-Zhen Qiu,
  • Rui-Hua Xu

摘要

Claudin-18 isoform 2 (CLDN18.2), a tight junction protein expressed in non-malignant gastric epithelium and exposed on tumor cell surface during malignant transformation, is a promising therapeutic target for gastric and gastroesophageal junction (G/GEJ) cancers. SHR-A1904 is an antibody–drug conjugate comprising CLDN18.2-targeting monoclonal antibody, a DNA topoisomerase I inhibitor payload and a cleavable peptide-based linker. We conducted a first-in-human, three-stage, phase 1 study to evaluate SHR-A1904 in 95 previously treated patients with CLDN18.2-positive advanced G/GEJ cancer. In the dose-escalation stage (0.6–8.0 mg kg−1), dose-limiting toxicities were observed in two patients at 4.8 mg kg−1 (grade 3 febrile neutropenia and grade 3 increased blood bilirubin) and in one patient at 6.0 mg kg−1 (grade 3 gastric mucosal lesion). The maximum tolerated dose was not reached, and 6.0 mg kg−1 and 8.0 mg kg−1 were selected for pharmacokinetic and efficacy expansion. Treatment-emergent adverse events occurred in all 95 patients, most commonly anemia (72 (75.8%)), nausea (64 (67.4%)), hypoalbuminemia (61 (64.2%)) and decreased white blood cell count (56 (58.9%)). Additionally, 59 patients (62.1%) experienced drug-related grade 3 or higher adverse events. No treatment-related deaths were reported. Among response-evaluable patients, the confirmed objective response rate was 24.2% (95% confidence interval (CI), 11.1–42.3) at 6.0 mg kg−1 and 25.0% (95% CI, 12.1–42.2) at 8.0 mg kg−1. The median progression-free survival was 5.6 months (95% CI, 3.0–6.9) at 6.0 mg kg−1 and 5.8 months (95% CI, 3.0–8.6) at 8.0 mg kg−1. In conclusion, SHR-A1904 demonstrated a manageable safety profile and encouraging anti-tumor activity in patients with CLDN18.2-positive G/GEJ cancer, warranting further investigation. ClinicalTrials.gov identifier: NCT04877717.