Abstract PO-028: Could pharmacodynamic modelling of FOLFIRINOX lead to more therapeutically advantageous treatment of pancreatic cancer?

Abstract

Abstract Pancreatic cancer is one of the most fatal human cancers with a 5-year survival rate of approximately 6%. Pancreatic Ductal Adenocarcinoma (PDAC) is the predominant (~90%) histological type among pancreatic cancers. The poor prognosis of PDAC is due to a combination of factors including late stage diagnosis at a locally advanced or metastatic stage, due to its asymptomatic progression. PDAC is a highly chemoresistant malignancy owing to its genetic heterogeneity and dense stromal environment. FOLFIRINOX (FFX) is a combinatorial chemotherapeutic approach consisting of 5-Fluorouracil (5-FU)/Leucovorin (LV), Irinotecan and Oxaliplatin, and is a first-line treatment option for pancreatic cancer patients. Despite its superior clinical benefit for the treatment of metastatic PDAC compared to gemcitabine, its high toxicity profile limits its use to patients with high performance status. In-depth pharmacodynamic (PD) modelling of the interactions between the individual agents of the regimen is required. Here, the effect of the FFX regime was investigated using both established and primary pancreatic cancer cell-lines cultured as 2D and 3D models. Cells were exposed to a concentration range of each agent in single, double and triple combinations. Cell viability assayed after 5 days. The addition of LV to 5-FU had no effect in vitro in Panc-1, Mia-PaCa-2 and primary PT99 cells, and was excluded from further analysis. The active metabolite of Irinotecan, SN-38, was used in-vitro. The Bliss Independent method was used to fit the cell viability data for all cell lines using SAS 9.4 software. A psi value less than 1 suggests synergistic interactions. Of 4 cell lines tested, MIA-PaCa-2 cells were the most sensitive to the agents of the FFX regimen, with the triple combination demonstrating synergistic interactions with a psi value of 0.036. However, in Panc-1, BxPC-3 and PT127 cells the triple combination was antagonistic, with psi values of 5.167, 3.598 and 5.349 respectively. For the double combination, Ox + SN-38 was shown to have synergistic interactions in 3 of 4 cell lines. The 5-FU + SN-38 and 5-FU + Ox combinations were synergistic in 3 of 4 cell lines. The differences in cellular response observed between the cell lines mirrors the heterogeneity of patients in the clinic and highlights the importance of mathematical modelling to better understand the PD interactions of multidrug treatment regimens. While the triple combinations were determined as antagonistic, meaning the net effect is less than the additive effect of individual agents, it still resulted in greater cell kill than any agent alone. Therefore despite findings of antagonism this further supports the need for all 3 drugs. In conclusion, the results suggest a complex interplay between the three agents, and the PD data could be used to assess whether lower doses and/or alternate dosing schedules would be feasible. This potentially translatable finding may result in FFX being available to more PDAC patients. Citation Format: Taylor Allen-Coyle, Jin Niu, Eva Welsch, Fiona O'Neill, Martin Clynes, Finbarr O'Sullivan, Donald E. Mager, Robert M. Straubinger, Sandra Roche. Could pharmacodynamic modelling of FOLFIRINOX lead to more therapeutically advantageous treatment of pancreatic cancer? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-028.