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

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 .

• Authors: Feng Wang, Ying Jin, Min Wang, Hui-Yan Luo, Wei-Jia Fang, Ying-Nan Wang, Yan-Xing Chen, Run-Jie Huang, Wen-Long Guan, Ji-Bin Li, Yu-Hong Li, Feng-Hua Wang, Xiao-Hua Hu, Yan-Qiao Zhang, Miao-Zhen Qiu, Lu-Lu Liu, Zi-Xian Wang, Chao Ren, De-Shen Wang, Dong-Sheng Zhang, Zhi-Qiang Wang, Wen-Ting Liao, Lin Tian, Qi Zhao, Rui-Hua Xu
• Journal: Nature medicine (Nat Med) Vol. 30 Issue 4 Pg. 1035-1043 (Apr 2024) ISSN: 1546-170X [Electronic] United States
• PMID: 38438735 (Publication Type: Randomized Controlled Trial, Clinical Trial, Phase II, Journal Article)
• Copyright: © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Aminopyridines
• Antibodies, Monoclonal
• Benzamides
• Bevacizumab
• Histone Deacetylase Inhibitors
• N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
• Programmed Cell Death 1 Receptor
• Vascular Endothelial Growth Factor A

Topics

• Humans
• Aminopyridines
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzamides
• Bevacizumab (adverse effects, therapeutic use)
• Colorectal Neoplasms (drug therapy, genetics)
• Histone Deacetylase Inhibitors (adverse effects, therapeutic use)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
• Tumor Microenvironment
• Vascular Endothelial Growth Factor A