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Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial

Abstract

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg−1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6–62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79–19.12), 8.18 months (95% CI = 6.67–10.48) and 17.48 months (95% CI = 12.35–26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67–not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63–31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027

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Fig. 1: Trial profile.
Fig. 2: Reduction in tumor burden and tumor responses from baseline.
Fig. 3: Kaplan–Meier estimates of PFS and OS.

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Data availability

The full study protocol is available in the 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 requests for clinical data should be addressed to J.J. (Jijiafu@hsc.pku.edu.cn). 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 re-identification.

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Acknowledgements

This study was supported by Akeso Biopharma. Additional funded grants were supported by the National Natural Science Foundation of China (no. 92259302 to J.J.; no. 82373438 to Z.L.; no. 82272655 to X.G.), the Peking University Medicine Fund for world’s leading discipline or discipline cluster development (no. BMU2022XKQ004 to J.J.), the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD&RPP-MRI, no. JYY2023-3 to Z.L.) and Peking University Clinical Scientist Training Program (no. BMU2023PYJH006 to X.G.). We thank the patients, their families, the investigators and research staff who participated in this study. We thank X. Ying at the Johns Hopkins Bloomberg School of Public Health for providing a statistical opinion of our study.

Author information

Authors and Affiliations

Authors

Contributions

J.J., Z.L., L.S. and X.G. contributed to study conception and design. All authors recruited the participants and provided the study materials. Z.Y., W.L., Z.M.W., B.L. and M.X. participated in the study and provided a substantial intellectual contribution to study design, data collection, data analysis, data interpretation and manuscript writing. All authors interpreted the data. All authors reviewed and approved the submitted version of the manuscript and are accountable for their contributions and the integrity of the work.

Corresponding authors

Correspondence to Lin Shen, Ziyu Li or Jiafu Ji.

Ethics declarations

Competing interests

L.S. reports consulting fees from Mingji Biopharmaceutical, Haichuang Pharmaceutical and Herbour Biomed; grants or contracts from Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), ALPHAMAB ONCOLOGY, Yaojie Ankang (Nanjing) Technology, Beigene, Qiyu Biotechnology (Shanghai) and BriSTAR Immunotech; and participation on a data safety monitoring board or advisory board for MSD, Merk, Bristol Myers Squibb, Boehringer Ingelheim, Sanofi, Roche, SERVIER and AstraZeneca. Z.Y., W.L., Z.M.W., B.L. and M.X. are employees of Akeso Biopharma. The remaining authors declare no competing interests.

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Nature Medicine thanks Yelena Janjigian, Shumei Kato, Sze-Huey Tan 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 Serum concentration–time curve after the first dose of cadonilimab.

Time (days) was presented on the X axis, cadonilimab concentration was presented on the Y axis. Data represented the mean and standard deviation of patients. (a) Linear curve after the first dose. (b) Semi-log curve after the first dose.

Extended Data Fig. 2 Serum concentration–time curve after the fifth dose of cadonilimab.

Time (days) was presented on the X axis, cadonilimab concentration was presented on the Y axis. Data represented the mean and standard deviation of patient. (a) Linear curve after the fifth dose. (b) Semi-log curve after the fifth dose.

Extended Data Fig. 3 PD-1/CTLA-4 receptor occupancy (RO) following multiple doses of cadonilimab in combination with chemotherapy.

Visit days were presented on the X axis, percent RO on the Y axis; Plot points were observed data. The boxplots represented median (bold line) and 25th and 75th percentiles of RO distribution. All visits were predose, except for C1D8. 1 cycle = 2 weeks for Q2W or 1 cycle = 3 weeks for Q3W.

Extended Data Table 1 Summary of best overall response based on RECIST v.1.1 in participants with response according to CPS
Extended Data Table 2 Summary of exposure to cadonilimab in all treated participants
Extended Data Table 3 Summary of safety analysis in each cohort
Extended Data Table 4 Adverse events that occurred in at least 5% of all treated participants
Extended Data Table 5 Summary of arithmetic means (s.d.) of PK parameters after first dose of cadonilimab in combination with chemotherapy
Extended Data Table 6 Summary of arithmetic means (s.d.) of pharmacokinetic parameters after the fifth dose of cadonilimab in combination with chemotherapy
Extended Data Table 7 Summary of ADA after the dose of cadonilimab in combination with chemotherapy

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2 and Study Protocol.

Reporting Summary

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Gao, X., Ji, K., Jia, Y. et al. Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03007-5

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