Abstract
Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg−1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95% confidence interval (CI) 0.54–0.81; P < 0.001) than the placebo group. The primary endpoint was met. The median progression-free survival was 7.0 months versus 5.3 months (HR 0.53, 95% CI 0.44–0.65). The median OS in patients with a PD-L1 combined positive score ≥5 was 15.3 months versus 10.9 months (HR 0.58, 95% CI 0.41–0.82). The objective response rate was 65.2% versus 48.9% with a median duration of response of 8.8 months versus 4.4 months. Grade ≥3 treatment-related adverse events occurred in 65.9% of the cadonilimab group and 53.6% of the placebo group, and the most common were decreased platelet count, decreased neutrophil count and anemia. Most of the immune-related adverse events were grade 1 or 2. No new safety signals were observed. Cadonilimab plus chemotherapy significantly improved OS with a manageable safety profile in patients with advanced G/GEJ adenocarcinoma. ClinicalTrials.gov registration: NCT05008783.
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Data availability
The full study protocol is available in Supplementary Information. Any data and material sharing will need approval from the ethics committees of the research centers, which will review requests for additional clinical data. Researchers can expect a response to their request within 1 month of receipt of the request. Any data requests should be addressed to the corresponding author. Individual anonymized participant data will be considered for sharing once the product and indication have been approved by major health authorities, if there is legal authority to share the data and there is no reasonable likelihood of participant reidentification.
Change history
26 March 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41591-025-03666-y
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Acknowledgements
Akeso Biopharma sponsored this study. Additional funded grants were provided by the National Natural Science Foundation of China (number 92259302 to J. Ji; number 82373438 to Z. Li; number 82272655 to X.G.), the Peking University Medicine Fund for World’s Leading Discipline or Discipline Cluster Development (number BMU2022XKQ004 to J. Ji), the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD&RPP-MRI, number JYY2023-3 to Z. Li), the Peking University Clinical Scientist Training Program (number BMU2024PYJH023 to X.G.) and the Youth Beijing Scholar 2024 (number 073 to X.G.). The sponsor worked with the investigators and participated in the study design, data collection, data analysis, data interpretation and review of the article. We thank the patients, their families, the investigators and the clinical teams who participated in the trial.
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L. Shen is the senior author. Y. Zhang, Z. Li, Xiaotian Zhang and X.G. contributed equally to this work and are joint first authors. J. Ji and L. Shen are the co-leading principal investigators. J. Ji, L. Shen, Z.Y., W. Liu, Z.M.W., B. Li and M. Xia conceived and designed the study. All investigators (J. Ji, L. Shen, Y. Zhang, Z. Li, Xiaotian Zhang, X.G., B. Liu, Yusheng Wang, Y. Ba, N.L., R.Z., Jingdong Zhang, Y.C., J.C., Mingzhu Huang, Y.F., Mulin Liu, Zheng Liu, J. Zhao, Wei Li, J.W., C.L., N.X., Z.G., B.C., L. Liu, P.N., L.W., L. Sheng, Zhenyang Liu, Y.H., K.G., G.W., W.W., F.Z., W.Q., J.G., J.Y., H.P., H.X., Y.Y., Y. Bai, Zhenghua Wang, J.X., X. Zhao, Hao Liu, Xizhi Zhang, W.D., H.X., Ming Liu, L.X., Y.T., J. Jin, X.Q., X.F., Mingwei Huang, H.C., Z. Zheng, Ying Wang, D.W., X.L., G.Y., Haiyan Liu, Y. Zhou, D.Z., S.Z., M.K., M.W., Y.G., Wenxin Li, Zejun Wang, M.Z., Jinghua Zhang, Q.L., S.S., A.Z., L. Lin, M. Xie, Z. Zhuang and T.Z.) contributed to the acquisition of data. J. Ji, L. Shen, Z.Y., W. Liu, Z.M.W., B. Li, M. Xia, Jiajia Zhang, X.Y. and D.M.P. contributed to the analysis or interpretation of data. D.L. and M. Hu performed statistical analysis. L. Shen drafted the paper. All authors contributed to the revision of the paper and approved the final draft. J. Ji and L. Shen jointly supervised this work. The corresponding author attests that all listed authors meet the authorship criteria.
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L. Shen reports receiving grants or contracts from Beigene, Ltd. and participating in a data safety monitoring board or an advisory board from MSD, Boehringer Ingelheim, SERVIER, AstraZeneca and Transcenta Holding Limited. Z.Y., D.L., W. Liu, M. Hu, Z.M.W., B. Li and M. Xia are employees of Akeso Biopharma. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Duration of response in the intention-to-treat population.
Kaplan—Meier estimates the duration of response in all randomised populations (a), in patients with PD-L1 CPS of 5 or higher (b), and in patients with PD-L1 CPS of less than 5 (c). Tick marks indicate censored data. CI, confidence interval; PD-L1, programmed death ligand 1; CPS, combined positive score.
Extended Data Fig. 2 Forest plot for subgroup analysis of progression-free survival.
A forest plot of the analyses in prespecified key subgroups in the intention-to-treat population. Data are presented as unstratified hazard ratios and 95% CI. The dashed line indicates a hazard ratio of 1.00. ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; PD-L1, programmed death ligand 1; CPS, combined positive score; CI, confidence interval.
Extended Data Fig. 3 Supplementary analysis of overall survival in the intention-to-treat population.
Kaplan-Meier curves showing overall survival in all randomised patients (a), in patients with PD-L1 CPS of 5 or higher (b), and in patients with CPS of less than 5 (c). Survival time was censored at the starting date of subsequent anticancer therapy if patients received PD-1/PD-L1 inhibitors for more than 2 months. The specific analysis methods were the same as those used in the primary analysis. CI, confidence interval; NR, not reached; NE, not estimable; PD-L1, programmed death ligand 1; CPS, combined positive score.
Extended Data Fig. 4 Subgroup analysis of overall survival by PD-L1 CPS with cadonilimab plus chemotherapy versus chemotherapy.
Forest plot shows results of overall survival in subgroup of the PD-L1 CPS population. Data are presented as unstratified hazard ratios and 95% CI. PD-L1, programmed death-ligand 1; CPS, combined positive score; CI, confidence interval.
Supplementary information
Supplementary Information
Supplementary Tables 1 and 2, list of investigators and study protocol.
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Shen, L., Zhang, Y., Li, Z. et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med (2025). https://doi.org/10.1038/s41591-024-03450-4
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DOI: https://doi.org/10.1038/s41591-024-03450-4