Abstract
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.
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Data availability
Data can be made available under restricted access due to proprietary reasons. The individual de-identified patient data generated during this study will be considered for sharing after the product and indication have been approved by major health authorities. Data may be requested 24 months after study completion. Qualified researchers should submit a proposal to the corresponding authors (R.-H.X., xurh@sysucc.org.cn; M.-Z.Q., qiumzh@sysucc.org.cn) outlining the reasons for requiring the data. The leading clinical site and sponsor will respond to requests in approximately 8 weeks. The sponsor will provide the data if the proposal is approved, provided that the requestor signs a data access agreement. Use of data must comply with the requirements of the Human Genetics Resources Administration of China and other country-specific or region-specific regulations. The study protocol and the statistical analysis plan are provided in the Supplementary Information.
Code availability
No custom code was used for data analysis in this study.
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Acknowledgements
This study was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd. This trial was designed by the authors in collaboration with the sponsor. The authors and sponsor were involved in data collection, analysis and interpretation; in guaranteeing the accuracy and completeness of the data; in writing of the report; and in the decision to submit the manuscript for publication. The sponsor had no right to veto publication or to control the decision regarding to which journal the manuscript was submitted. We are grateful to all patients, their families, the investigators, the site staff and the trial teams. Medical writing support was provided by H. Dong (medical writer at Hengrui) according to Good Publication Practice guidelines.
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R.-H.X. has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: R.-H.X. Acquisition, analysis and interpretation of data: all authors. Drafting of the manuscript: D.-Y.R. and H.-X.W. Critical revision of the manuscript for important intellectual content: R.-H.X., M.-Z.Q., S.-X.L., W.-W.H., X.-J.L., Z.-X.N., Q.D., H.-L. Li, Z.-Y.P., H.-X.L., Y.-Q.Z., X.-Y.L., X.-Y.X., S.-R.C., Y.-G.D., J.Z., Z.L., H.-T.L., X.W., Y.Z., L.L., H.-L. Liu, P.-S.X., A.-L.S., R.-N.J., Y.-Q.L., X.-D.P., S.-C.W., A.-A.Y. and J.X. Statistical analysis: A.-A.Y. Administrative, technical or material support: R.-H.X., M.-Z.Q., D.-Y.R., H.-X.W., S.-C.W., A.-A.Y. and J.X. Supervision: R.-H.X. and M.-Z.Q.
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R.-H.X. has served in a consulting or advisory role for Bristol Myers Squibb, Merck Serono, Roche, Astellas, AstraZeneca, Junshi, Hengrui, BeiGene and CPPC. S.-C.W., A.-A.Y. and J.X. are employed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. The other authors declare no competing interests.
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Nature Medicine thanks Sarbajit Mukherjee and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ulrike Harjes, in collaboration with the Nature Medicine team.
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Extended data
Extended Data Fig. 1 Incidence of Vomiting and Nausea With or Without Prior Gastrectomy.
TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event.
Extended Data Fig. 2
Occurrence of Treatment-Related Nausea and Vomiting During Study.
Extended Data Fig. 3 Pharmacokinetic Profile.
(a) Mean serum concentration versus time curve of SHR-A1904 over cycles 1 to 3 at doses of 0.6, 1.2, 2.4, 3.6, 4.8, 6.0, and 8.0 mg/kg. (b) Mean serum concentration versus time curve of SHR-A1904, free payload, and total antibody over cycles 1 to 3 at dose of 6.0 and 8.0 mg/kg. Error bars indicate SD.
Extended Data Fig. 4
Kaplan-Meier Plots of Overall Survival in All Patients.
Extended Data Fig. 5 Correlation Between CLDN18.2 Expression and Anti-tumor activity of SHR-A1904.
CLDN18.2, claudin-18 isoform 2; ORR, objective response rate.
Supplementary information
Supplementary Information (download PDF )
Supporting preclinical data, Protocol and Statistical analysis plan.
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Ruan, DY., Wu, HX., Luo, SX. et al. The antibody–drug conjugate SHR-A1904 for targeting CLDN18.2 in advanced gastric or gastroesophageal junction cancer: a phase 1 trial. Nat Med 31, 3037–3046 (2025). https://doi.org/10.1038/s41591-025-03781-w
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DOI: https://doi.org/10.1038/s41591-025-03781-w
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