Abstract 846: Utilizing quantitative systems pharmacology (QSP) model to understand cytokine release syndrome (CRS) following administration of epcoritamab in DLBCL patients
Authors: Afzal Nasrin , Li Tommy , Chiu Christopher , Sacchi Mariana , Gupta Manish , Xu Steven , Thalhauser Craig J. 
Published: April 2023

Abstract
Background: Epcoritamab is a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells (1). Epcoritamab’s pharmacokinetics (PK), pharmacodynamics, and safety profiles were investigated in GCT3013-01 escalation study across a wide range of doses. CRS is an adverse event of special interest for T cell engagers such as Epcoritamab. As such, step-up dosing (SUD) has been investigated in study GCT3013-01 escalation to minimize release of cytokines and mitigate severe CRS symptoms. Seventeen permutations of SUD were tested, with doses ranging from 0.004 to 60 mg. Based on observed CRS data, a SUD regimen of 0.16/0.8/48 mg was selected. The aim of the analysis was to develop a QSP model capable of predicting cytokine release which can be used to identify potential optimal SUD regimen.
Method: Leveraging Epcoritamab preclinical and clinical data, we have developed a QSP platform that captures the observed tumor responses and allows for systemic predictions of biomarkers with the selected SUD regimen. A minimal physiologically based PK model was linked to submodels of T cell activation, proliferation, and cytotoxicity of target-bearing cells, to create an integrated QSP model of the DLBCL system. Epcoritamab-mediated cross-linking of target(s) and CD3 receptor to form trimer complexes drives cell trafficking and cytokine production as well as inducing death of target-bearing cells. The model described the PK, cellular effects, and observed cytokine profiles within the plasma, and simulated similar effects in lymph node(s), tumor, and other peripheral body tissue.
Result: After SC administration of Epcoritamab, transient and modest elevation of selected cytokines was observed. Patients’ cytokine profiles were categorized into three different trends based on Cycle 1 data. By accounting for the interaction of receptors and ligands at the nano-scale level (time and physical size) we characterized the dose response and dynamics of T cells, B cells, IL6, and IL10 in patients enrolled in the study by using the QSP model.
Conclusions: This analysis integrated underlying mechanisms to predict various systemic biomarkers dynamics including T cells, B cells, IL6 and IL10 following administration of Epcoritamab. The well-studied pathways and mechanisms allow implementation of the model in disease indications other than DLBCL.
References: 1. M. Hutchings, et. al, (2021) Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study, The Lancet, Vol. 398, Issue 10306, P1157-1169.
Citation Format: Nasrin Afzal, Tommy Li, Christopher Chiu, Mariana Sacchi, Manish Gupta, Steven Xu, Craig J. Thalhauser. Utilizing quantitative systems pharmacology (QSP) model to understand cytokine release syndrome (CRS) following administration of epcoritamab in DLBCL patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 846.