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Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial

Nature Medicine volume 30, pages 708–715 (2024)Cite this article

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Abstract

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360–0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655.

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Fig. 1: Trial profile.
Fig. 2: Kaplan–Meier curves.
Fig. 3: HRs with 95% CIs for RFS in different patient subgroups.

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Data availability

The study protocol is available in the Supplementary Information. The datasets of the clinical trial may be requested 12 months after the publication of this article. Researchers who wish to request access to raw and analyzed data should send an email to the corresponding authors (S.-Q.C. and Y.-F.L.), with a clear indication of the research purpose. Requests will be reviewed by the institutional review board, considering the risk of patient reidentification, and a response can be expected within 14 days. Individual deidentified data of the participants are available for approved eligible applications and investigators after signing a data access agreement. Source data are provided with this paper.

Code availability

R software was used for data analysis (‘survminer’ package, ‘tableone’ package, http://www.r-project.org/).

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2022YFC2503705 to S.-Q.C.), Shanghai Municipal Health Commission (2023ZZ02005 to S.-Q.C.) and the National Natural Science Foundation of China (82072618 to S.-Q.C.). The funders had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

Author information

Author notes

  1. These authors contributed equally: Kang Wang, Yan-Yun Xiang, Hong-Ming Yu, Yu-Qiang Cheng, Zong-Han Liu.

  2. These authors jointly supervised this work: Yan-Fang Liu, Shu-Qun Cheng.

Authors and Affiliations

  1. Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China

    Kang Wang, Yan-Jun Xiang, Hong-Ming Yu, Yu-Qiang Cheng, Zong-Han Liu, Jie Shi, Wei-Xing Guo, Chong-De Lu, Ya-Xin Zheng, Fei-Guo Zhou & Shu-Qun Cheng

  2. Shanghai Hepatobiliary Cancer Research Center, Naval Medical University, Shanghai, China

    Kang Wang, Hong-Ming Yu, Yu-Qiang Cheng & Shu-Qun Cheng

  3. National Key Laboratory of Medical Immunology, Institute of Immunology, Naval Medical University, Shanghai, China

    Yan-Jun Xiang & Yan-Fang Liu

  4. Department of Health Statistics, Naval Medical University, Shanghai, China

    Ying-Yi Qin

  5. Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China

    Mao-Lin Yan

  6. Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing College, Jiaxing, China

    Hong-Kun Zhou

  7. Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Chao Liang

  8. Department of Hepatobiliary Surgery, Affiliated Hospital of Binzhou Medical College, Binzhou, China

    Fan Zhang

  9. Department of General Surgery, Taiyuan People’s Hospital, Taiyuan, China

    Wen-Jing Wei

  10. Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

    Wan Yee Lau

  11. CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Jing-Jing Li

  12. Department of Pathology, Changhai Hospital, Naval Medical University, Shanghai, China

    Yan-Fang Liu

  13. Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, China

    Shu-Qun Cheng

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Contributions

S.-Q.C., Y.-F.L. and K.W. were responsible for study conception and design, project supervision, quality assessment, review, and approval of the article. Y.-J.X., H.-M.Y., Y.-Q.C. and Z.-H.L. contributed to the design of the clinical trial, writing of the protocol, recruitment and treatment of the patients, management of the trial and data, analysis and interpretation of data, and writing and final approval of the paper. J.S., W.-X.G., C.-D.L., Y.-X.Z., F.-G.Z. and J.-J.L. accessed and verified the data. M.-L.Y., H.-K.Z., C.L., F.Z. and W.-J.W. were involved in the design of the clinical trial, recruitment and treatment of the patients, management of the trial and data, and review of the paper. W.Y.L. accessed and verified the data and reviewed the paper. Y.-Y.Q. was responsible for statistical analysis and interpretation and the data review. All authors read and approved the final draft of the paper.

Corresponding authors

Correspondence to Yan-Fang Liu or Shu-Qun Cheng.

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Nature Medicine thanks Fei Liang, David Pinato and Arndt Vogel 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 Adjusted Kaplan-Meier curves of RFS for patients in the sintilimab and active surveillance groups.

HR, two-sided 95%CI and P value were estimated using the Cox proportional hazards method. Cox proportional hazards regression model adjustment for cirrhosis and microvascular invasion stage. Abbreviations: RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval.

Source data

Extended Data Fig. 2 HRs (center square) with 95% CIs (error bars) for OS in different patient subgroups.

HRs with two-sided 95%CIs were calculated using the Cox proportional hazards method. Abbreviations: RFS, recurrence-free survival; HR, hazard ratio; CI, confidence interval; AFP, alpha-fetoprotein; DCP, des gamma-carboxy prothrombin.

Source data

Extended Data Table 1 Details of the surgical procedure for the intention-to-treat population
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Extended Data Table 2 Events for recurrence-free survival
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Extended Data Table 3 Cox regression for recurrence-free survival
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Extended Data Table 4 Treatment after recurrence
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Extended Data Table 5 Adverse events regardless of attribution
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Extended Data Table 6 Immune-mediated adverse events requiring systemic steroids in the sintilimab group (n = 97)
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Extended Data Table 7 Adverse events that led to the discontinuation of sintilimab
Full size table

Supplementary information

Supplementary Information

Supplementary Table 1, protocol and CONSORT 2010 checklist.

Reporting Summary

Source data

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 2

Statistical source data.

Source Data Extended Data Table 3

Statistical source data.

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Wang, K., Xiang, YJ., Yu, HM. et al. Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial. Nat Med 30, 708–715 (2024). https://doi.org/10.1038/s41591-023-02786-7

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