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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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.
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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.
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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.
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.
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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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DOI: https://doi.org/10.1038/s41591-023-02786-7
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