PO-264 Preclinical studies with pegvorhyaluronidase alfa (PEGPH20) in combination with FOLFIRINOX (FFX) chemotherapy in models of pancreatic ductal adenocarcinoma

Abstract

IntroductionHyaluronan (HA) accumulates in the tumour microenvironment (TME) of many solid tumours and has been associated with tumour progression and negative clinical outcomes. Pegvorhyaluronidase alfa (PEGPH20, P) is a novel biologic that enzymatically degrades HA. In preclinical models, P-mediated enzymatic degradation of HA is associated with decreased tumour interstitial fluid pressure, increased tumour perfusion, and increased access and anti-tumour efficacy of cytotoxic and immunotherapies. As pancreatic ductal adenocarcinoma (PDA) has been identified as a cancer type that accumulates high levels of HA, here we evaluated whether P alters the activity of the cytotoxic components of FOLFIRINOX (FFX), a common therapeutic regimen for advanced PDA, on human and murine PDA cells. We also evaluated p+FFX in vivo anti–tumour activity in BxPC3/HAS3, a HA accumulating human PDA model.Material and methodsFor in vitro experiments, fluorouracil, irinotecan and oxaliplatin were evaluated individually and in combination in both 2D culture and 3D tumour spheroids. For in-vivo evaluation, mice were inoculated with BxPC3/HAS3 cells adjacent to the right tibial periosteum and tumour growth was monitored via ultrasonography. When tumours reached ~230 mm3, mice (n=8/group) were staged into treatment groups: 1) vehicle; 2) 0.0375 mg/kg P BIW; 3) low FFX - 30 mg/kg leucovorin, 15 mg/kg fluorouracil, 30 mg/kg irinotecan, and 1.2 mg/kg oxaliplatin QW; 4) high FFX - 65 mg/kg leucovorin, 32.5 mg/kg fluorouracil, 65 mg/kg irinotecan, and 2.6 mg/kg oxaliplatin QW; 5) p+low FFX; and 6) p+high FFX. FFX was administered 24 hour after P.Results and discussionsPDA cells were more sensitive to chemotherapy treatment in 2D than 3D culture. The TME-modifying enzyme P did not show an effect on chemotherapy sensitivity, whether tested as individual or combined cytotoxics. In the BxPC3/HAS3 model, P increased the anti-tumour efficacy of low FFX 4-fold (56.3% vs. 11.3% tumour growth inhibition [TGI], respectively) and extended median survival time (MST) by >36% (32d vs. 23.5d, respectively), whereas P increased the efficacy of high FFX by 61% (64.3% vs. 39.8% TGI, respectively) and extended MST by 12.5% (36d vs. 32d, respectively). A maximum 5% BW loss was observed following the initial FFX dose.ConclusionTaken together, the results suggest that P does not affect the cytotoxic activity of FFX components on PDA cells in culture, and that P-mediated HA degradation improves the anti-tumour efficacy of FFX (especially suboptimal doses) in a preclinical PDA model.