Clinical and biological determinants of multimodal metronomic chemotherapy efficacy in chemo‐refractory gastrointestinal cancers

The treatment of chemo-refractory metastatic gastrointestinal carcinoma is a consequential medical need still unmet, and the presence of a tumor-permissive environment is recognized as the main resistance factor. Metronomic administration of chemotherapy might be a simple strategy to target the tumor microenvironment, circumvent angiogenesis, and deplete immune suppressive cells. However, the efficacy of metronomic chemotherapy (MC) in chemo-refractory gastrointestinal cancers and its mode of action remain elusive. Multimodal MC was administered continuously, combining low doses of capecitabine, cyclophosphamide, and aspirin. Plasma and peripheral blood mononuclear cells were collected at baseline and after treatment to identify tumor microenvironment-related biomarkers ("Epitopes-CRC01" trial, NCT02838381). Seventy-seven heavily pretreated patients received MC with no new safety signal and a median progression-free survival (PFS) of 2.8 months (95% CI = 2.4-3.0 months). A total of 28 patients had a PFS beyond 3 months and were defined as "responders", including 15 patients with a PFS beyond 6 months. Liver metastases were present in 69.4% of non-responders versus 28.6% of patients with a PFS >3 months (p < .001). An increased PD1 expression on CD4 and CD8 T-cells was significantly observed in responders and associated with better survival (p = .025). At baseline, Ang2^Low/CXCL14^High group displayed a longer PFS (p = .019). Multimodal MC is effective and bioactive in gastrointestinal cancers. The presence of liver metastases, baseline plasmatic levels of Ang2 and CXCL14, as well as the induction of PD1 on T-cells are potential biomarkers for efficacy. These results feature a potential subset of diseases where MC might be a promising cost-effective and well-tolerated therapeutic option.