Abstract 2691: A triple combination of fostrox (MIV-818) with immune checkpoint and kinase inhibition shows increased anti-tumor efficacy in vivo

Background: Fostroxacitabine bralpamide (fostrox) is an orally administered liver-targeted troxacitabine-based nucleotide prodrug currently undergoing phase 1/2a clinical trial in advanced hepatocellular carcinoma (HCC), in combination with pembrolizumab or lenvatinib (NCT03781934). In phase 1 monotherapy fostrox has demonstrated proof-of-concept in advanced HCC, intrahepatic cholangiocarcinoma and liver metastasis from gastrointestinal solid tumors. Liver-selective fostrox-induced DNA-damage and tumor cell killing has the potential to enhance the anti-tumor activity in combination with checkpoint blockade, and inhibition of angiogenesis leads to increased levels of the active metabolite of fostrox. We therefore investigated a triple combination of fostrox with anti-PD1 and lenvatinib in nonclinical tumor models in vivo. Methods: Combinations of fostrox with anti-PD1 and lenvatinib treatment were evaluated in the subcutaneous syngeneic mouse CT26 model1. Groups of 8 mice were randomized using the Matched Distribution method based on tumor size day 1. Treatment was with fostrox (BID days 1-5, p.o.), anti-PD1 (BIW for 3 weeks, i.p.), and lenvatinib (QD for 21 days, p.o.). Tumours were measured three times weekly during the dosing phase, and statistical differences between the treatment groups was analyzed by two-way ANOVA. Pharmacodynamic response to fostrox, induction of DNA-damage (phospo-ser139-H2AX), was assessed by immunohistochemistry (IHC). Tumor infiltrating lymphocytes (TILs) were assessed by IHC evaluating the expression level of CD8, CD4, LAG-3, and PD-L1. Results: Treatment with the triple combination of fostrox (30mg/kg) plus anti-PD1 (3mg/kg) and lenvatinib (5mg/kg) showed a significantly (p