Modulation of lipid metabolism associated with response to metronomic capecitabine plus camrelizumab in patients with refractory gastrointestinal cancer: A prospective, single-center, exploratory trial.
Authors: Zhou Chenfei , Yin Yuanyuan , Shangguan Chengfang , Shi Min , Cai Qu , Ji Jun , Zhang Xuekun , Sun Yan , Rensen Sander S.M. , Olde Damink Steven W.M. , Zhu Zhenggang , Zeng Rong , Zhang Jun 
Published: October 2024

2616

Background:
Metronomic chemotherapy which can modulate tumor microenvironment is a potential partner of PD-1 antibodies. The association between lipid metabolism and efficacy of immunotherapy is recognized but has not been reported in metronomic chemotherapy. We aimed to evaluate the feasibility of metronomic capecitabine plus camrelizumab as a salvage treatment for refractory gastrointestinal cancer patients and to explore the involvement of lipid metabolism in response to this combination therapy.
Methods:
In this single-center, exploratory trial, advanced GI cancer patients who had disease progression after standard chemotherapy were treated with metronomic capecitabine (500mg twice daily) plus camrelizumab (200mg on day 1 intravenously every 2 weeks). The primary endpoint was safety. For lipid metabolism, body composition analysis based on CT scans at L3 level and peripheral blood lipidomic analysis were performed. Associations between treatment efficacy and body composition parameters as well as differential plasma lipids were assessed. Plasma samples of GI cancer patients treated with PD-1 antibody-based therapy were detected by lipidomic analysis as a test cohort. Differential expressed genes of C2C12 cells treated with metronomic dose 5-fluorouracil
in vitro
were detected and pathway enrichment analysis was performed.
Results:
Twenty-six patients with esophageal (9), gastric (8), bile duct (5), or pancreatic cancer (3) were enrolled. Sixteen patients (61.5%) had ≥2 previous lines of chemotherapy and 11 patients were ECOG 2. Treatment emergent adverse events (TEAEs) grade ≥3 occurred in five patients (19.2%), including biliary tract infection (11.5%), fatigue (7.7%), and increased AST/ALT (3.8%). Three patients suffered severe AEs that were not related to treatment. 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 of patients. Differential plasma lipids were identified in disease-controlled patients compared with those achieved disease progression. High level of a plasma 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) indicated better survival of patients and was confirmed in the test cohort. Differential plasma lipids were increased after treatment. Differential expressed genes in C2C12 cells after treatment were involved in lipid metabolism pathways.
Conclusions:
Metronomic capecitabine plus camrelizumab showed low rate of grade ≥3 AEs and promising efficacy in refractory GI cancer patients. Lipid metabolism modulation was associated with treatment response to this combination therapy.

Clinical trial information:
NCT04508686
,
NCT04510818
,
NCT04932187

.