Lipid metabolism associated with efficacy of metronomic capecitabine and camrelizumab in gastrointestinal cancer: an exploratory clinical trial.

Chenfei Zhou, Yuanyuan Yin, Chengfang Shangguan, Qingqing Wu, Qu Cai, Wenqi Xi, Liting Guo, Jinling Jiang, Min Shi, Junwei Wu, Jun Ji, Xuekun Zhang, Yan Sun, Sander S M Rensen, Steven W M Olde Damink, Zhenggang Zhu, Rong Zeng, Jun Zhang

Journal: BMC medicine 2025;23(1):572

PMID: 41121239

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Abstract

BACKGROUND

Metronomic chemotherapy shows potential to enhance efficacy of PD-1 antibodies but has not been assessed in gastrointestinal (GI) cancer. Immunotherapy efficacy can be affected by body composition and lipid metabolism of patients. We aimed to evaluate the feasibility of metronomic capecitabine plus camrelizumab as a salvage treatment of late-stage GI cancer and to explore the roles of body composition and lipid metabolism in this regimen.

METHODS

This is a single-center, exploratory trial. Eligible GI cancer patients who had disease progression after standard chemotherapy were treated with metronomic capecitabine (500 mg twice daily) plus camrelizumab (200 mg on day 1 intravenously every 2 weeks). The primary endpoint was safety. Body composition indices analyzed by SliceOmatic software and lipidomics analyses using liquid chromatography-mass spectrometry were performed as exploratory investigation. Differentially expressed genes (DEGs) of C2C12 myocytes treated with metronomic dose 5-fluorouracil were detected by RNA sequencing.

RESULTS

A total of 26 patients were enrolled. Treatment emergent adverse events (TEAEs) grade ≥ 3 occurred in five patients (19.2%). Objective response rate was 19.2% (5/26), including two patients with complete response. High skeletal muscle radiation attenuation (SMRA) was associated with disease control and better survival. Differential plasma lipids were identified in disease-controlled patients compared with those who showed disease progression. High levels of a 6-lipid signature composed of SM40:1;3, TG54:4-FA20:2, LPC(16:0), TG52:0-FA20:0, TG56:3-FA20:2, and PE(P-18:1/18:2) were associated with better survival. SMRA and this plasma lipid panel were both increased in disease-controlled patients after treatment. DEGs including prkg1, adora1, and Il15 in metronomic 5-FU treated C2C12 myocytes could be enriched into lipid metabolism pathways.

CONCLUSIONS

Metronomic capecitabine plus camrelizumab is well tolerated and shows promising efficacy in GI cancer. SMRA and specific plasma lipids are associated with efficacy of this regimen and indicate the modulation effect of metronomic capecitabine on lipid metabolism.

TRIAL REGISTRATIONS

NCT04508686 (Aug 11, 2020), NCT04510818 (Aug 12, 2020), NCT04932187 (Sep 17, 2021).

Address: Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Surgery, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.; CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.; Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; CAS Key Laboratory of Systems Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.; Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Surgery, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.; Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Gastrointestinal Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Clinical Research and Trial Center, ShanghaiTech University, Shanghai, China. [email protected].; Shanghai Key Laboratory of Gastric Neoplasms, Shanghai, China. [email protected].; National Facility for Protein Science (Shanghai), Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China. [email protected].; Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].

DOI: 10.1186/s12916-025-04377-4

MeSH Terms: Humans, Capecitabine, Female, Male, Middle Aged, Aged, Lipid Metabolism, Gastrointestinal Neoplasms, Antibodies, Monoclonal, Humanized, Administration, Metronomic, Adult, Antineoplastic Combined Chemotherapy Protocols, Body Composition