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Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial

Nature Medicine volume 30, pages 1035–1043 (2024)Cite this article

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Abstract

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239.

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Fig. 1: Consort diagram and patient categorization for the CAPability-01 study.
Fig. 2: Duration of exposure and response in the doublet and triplet arms.
Fig. 3: Data on response rates and long-term outcomes.
Fig. 4: A ‘hotter’ tumor microenvironment in the triplet therapy group.

Data availability

Our study is compliant with the ‘Guidance of the Ministry of Science and Technology of China for the Review and Approval of Human Genetic Resources’. The RNA sequencing data from patients reported in this paper have been deposited into the Genome Sequence Archive in the National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences, under the project accession number PRJCA009109 with restricted access, and will be made available only upon request for academic use and within the limitations of the provided informed consent. Request can be obtained by completing the application form via the GSA-Human System. For detailed guidance on making a data access request, see GSA-Human_Request_Guide_for_Users (https://ngdc.cncb.ac.cn/gsa-human/document/GSA-Human_Request_Guide_for_Users_us.pdf) and the approximate response time for accession requests is 14 days. The full clinical dataset generated in this study is not publicly available. All requests for clinical data will be reviewed by the Sun Yat-Sen University Cancer Center to verify whether the request is subject to any confidentiality obligations. Requests for additional clinical data should be emailed to the corresponding author with detailed proposals for approval. Individual patient-level raw data containing identifiable patient information cannot be shared.

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Acknowledgements

This study was funded by Innovent Biologics, Inc. and Shenzhen Chipscreen Biosciences Co., Ltd. We thank the patients and their families for participating in the study. R.H.X. discloses support for the research of this work from the National Natural Science Foundation of China (82321003, 81930065, 82173128); CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-036); Sun Yat-sen University Clinical Research 5010 Program (84000-31630002); and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0004). F.W. discloses support for the publication of this work from the International Cooperation and Exchanges National Natural Science Foundation of China (82061160373); Science and Technology Program of Guangzhou (202206080011); Fundamental Research Funds for the Central Universities, Sun Yat-sen University (84000-31620003); and Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0018). We thank Sharvesh Raj Seeruttun (Sun Yat-sen University Cancer Center) for assistance in writing and revising the contents of this work.

Author information

Author notes

  1. These authors contributed equally: Feng Wang, Ying Jin, Min Wang, Hui-Yan Luo, Wei-Jia Fang.

Authors and Affiliations

  1. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, P. R. China

    Feng Wang, Ying Jin, Min Wang, Hui-Yan Luo, Ying-Nan Wang, Yan-Xing Chen, Run-Jie Huang, Wen-Long Guan, Yu-Hong Li, Feng-Hua Wang, Miao-Zhen Qiu, Zi-Xian Wang, Chao Ren, De-Shen Wang, Dong-Sheng Zhang, Zhi-Qiang Wang & Rui-Hua Xu

  2. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, P. R. China

    Feng Wang, Ying Jin, Min Wang, Hui-Yan Luo, Ying-Nan Wang, Yan-Xing Chen, Run-Jie Huang, Wen-Long Guan, Yu-Hong Li, Feng-Hua Wang, Miao-Zhen Qiu, Zi-Xian Wang, Chao Ren, De-Shen Wang, Dong-Sheng Zhang, Zhi-Qiang Wang & Rui-Hua Xu

  3. Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China

    Wei-Jia Fang & Lu-Lu Liu

  4. Department of Clinical Research, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China

    Ji-Bin Li

  5. Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China

    Xiao-Hua Hu

  6. Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, P. R. China

    Yan-Qiao Zhang

  7. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China

    Wen-Ting Liao & Lin Tian

  8. Bioinformatics Platform, Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China

    Qi Zhao

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  1. Feng Wang
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Contributions

F.W. and R.H.X. contributed to the conception and design of the study. F.W., Y.J., H.Y.L., W.J.F., W.L.G., Y.H.L., F.H.W., M.Z.Q., X.H.H., Y.Q.Z., L.L.L., Z.X.W., C.R., D.S.W., D.S.Z., Z.Q.W. and R.H.X. recruited and/or treated patients and gathered clinical data on efficacy and safety. J.B.L., Y.J. and W.L.G. analyzed the clinical data and performed statistical analyses. M.W., Y.N.W. and R.J.H. performed the experiment and data analyses. Y.X.C. and Q.Z. performed the bioinformatic analysis. W.T.L. and L.T. directed the experiment conduction. All authors interpreted the data. All authors had access to all the data in the study, participated in developing or reviewing the manuscript and provided final approval to submit the manuscript for publication.

Corresponding authors

Correspondence to Feng Wang or Rui-Hua Xu.

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Competing interests

R.H.X. has served as a consulting or advisory role for Bristol-Myers Squibb, Merck Serono, Roche, Astellas, and AstraZeneca. The remaining authors delcare no competing interests.

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Nature Medicine thanks Aparna Parikh, Sze-Huey Tan, Weiping Zou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Radiographic response in representative patients in the triplet arm.

a–d, The CT scans of four representative patients in the triplet arm at baseline and at the time of their best response.

Extended Data Fig. 2 Forest plot of overall survival in key subgroups with the triplet combination versus the doublet combination in patients.

A Cox regression model with an interaction term was employed to assess whether the feature influences the relative efficacy of triplet treatment compared to doublet treatment in terms of PFS. The interaction P value indicates the statistical significance of the interaction term in the Cox model, determined using a two-sided Wald test. Each rectangle within the plot represents the hazard ratios (HR) of the triplet group versus the doublet group in each subgroup, while the error bar accompanying the rectangle signifies the 95% confidence interval for each HR. NR, not reach. a Not reported, n = 3.

Extended Data Fig. 3 A stronger anti-tumor immune response after triplet therapy.

a–d, Gene Set Variation Analysis (GSVA) of class-I HLA signal (a), class-II HLA signal (b), cytokine signal (c), cytotoxic signal (d) comparing pre- and post-treatment tumors from the patients receiving doublet (n = 6, PD/SD = 6) or triplet (n = 4, PR/CR = 2, PD/SD = 2) therapy with bulk RNA sequencing. Each dot denotes a sample and each line denotes a patient. Horizontal lines inside the box represent the median; the top ends of the box represent the lower quartile; the bottom ends of the box represent the lower quartile; the whiskers above the box plot extend from the upper quartile to the highest actual value that is within the (75th percentile + 1.5 * (interquartile range)); the whiskers below the box plot extend from the lower quartile to the lowest actual value that is within the (25th percentile - 1.5 * (interquartile range)).

Supplementary information

Supplementary Information

Treatment-emergent adverse events in all patients.

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Wang, F., Jin, Y., Wang, M. et al. Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial. Nat Med 30, 1035–1043 (2024). https://doi.org/10.1038/s41591-024-02813-1

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