Biomarker dynamics in the completed phase I study of DT-9081: An analysis of ex vivo cytokine stimulation, urinary PGEM, and tumoral biomarkers in advanced solid tumors

Background: DT-9081, a novel EP4R-antagonist, recently completed its Phase I study in patients with advanced solid tumors (NCT05582850). In addition to establishing safety, tolerability, and pharmacodynamic signals, integrated biomarker analyses were conducted to gain insights into its mechanism of action and therapeutic potential. Objectives: This abstract presents a comprehensive evaluation of multiple biomarkers from the completed Phase I study of DT-9081. The analyses include:Ex vivo cytokine stimulation examining IL-10, IL-5, MIP-1alpha, and TNFalpha concentrationUrinary prostaglandin E metabolite (tetranor-PGEM) levels, measured by LC-MS/MS Tumor tissue expression of mPGES and COX2 enzymes, as well as PD-L1, assessed pre- and post-treatmentPlasma cytokine levels Methods: Peripheral blood mononuclear cells from subjects were isolated and subjected to ex vivo cytokine stimulation, with subsequent quantification of IL-10, IL-5, MIP-1alpha, and TNFalpha using validated immunoassays. Urine samples were analyzed for PGEM levels by LC-MS/MS. Tumor biopsies, collected at baseline and after treatment, were examined by multiplex immunofluorescence to determine the expression levels of mPGES, COX2, and PD-L1. Additionally, plasma samples were collected at serial timepoints, and cytokine concentrations were measured. Results:Biomarker assessments revealed that DT-9081 treatment modulated immune responses as evidenced by restauration of ex vivo cytokine release profiles (IL-10, IL-5, MIP-1alpha, and TNFalpha). Increase in urinary PGEM levels was consistent with modulation of the prostaglandin pathway. Tumor tissue analyses demonstrated alterations in the expression of mPGES and COX2 enzymes following treatment, and changes in PD-L1 expression were observed, suggesting potential implications for combination with immune checkpoint inhibitors. Plasma cytokine data provided additional evidence of systemic immunomodulation. Integrated analysis suggest that DT-9081 favors a Th1, antitumoral immune response. Conclusions: The integrated biomarker evaluation from the completed Phase I study of DT-9081 offers valuable insights into its immunomodulatory effects in advanced solid tumors. The combined analysis of ex vivo cytokine stimulation, urinary PGEM levels, and tumor biomarker expression (mPGES, COX2, and PD-L1) supports the engagement of multiple pathways involved in the anti-tumoral response after treatement with DT-9081. These results lay the groundwork for further clinical development and potential combination strategies in immuno-oncology. Keywords: DT-9081, EP4R antagonist, small molecule, solid tumors, immuno-oncology, phase I/ trial, biomarker, NCT05582850.