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Background: Epcoritamab, a bispecific antibody, binds to CD3 on T cells and CD20 on B cells to induce T-cell-mediated killing of CD20+ malignant B cells. For T-cell engagers, CRS is a potential adverse event. Step-up dosing (SUD) is used to mitigate potential severe CRS symptoms. Identification of optimal SUD is challenging because multiple steps of dose escalation are needed to manage CRS. Based on a dose-escalation study of epcoritamab, 2-step SUD (weekly priming and intermediate dose prior to administering the target dose) was necessary to effectively mitigate the risk of CRS. A wide range of priming (0.004-0.16 mg) and intermediate (0.0128-1.6 mg) doses for 17 combinations was explored; the 0.16/0.8/48-mg regimen was selected based on the CRS event rate. We further explored optimization of the SUD regimen using a model-based approach to inform clinical evaluation. Methods: A repeated time-to-event model was developed using pharmacokinetic and CRS event data collected in the phase 1/2 EPCORE NHL-1 monotherapy trial. The model was required to predict the onset of 1 or more CRS events (all-grade and grade ≥2) over time and to describe the impact of epcoritamab concentration on CRS risk over time and the development of tolerance after multiple doses. To capture these dynamics, the hazard function (risk of CRS event) was modeled as the product of 2 components: the first component addressed the risk of a CRS event and allowed for increasing hazard with increasing epcoritamab plasma concentrations, and the second component described the inhibition of the hazard to capture development of CRS tolerance over time after multiple doses. Simulations assessed the performance of different SUD regimens, measured by the probability of a grade ≥2 CRS event. Results: The model was able to predict the observed CRS events over time and confirmed that the SUD regimen used in the recommended phase 2 dose regimen for epcoritamab (0.16/0.8/48 mg) provided similar or better potential to reduce the risk of grade ≥2 CRS events versus other priming and intermediate dose permutations tested during dose escalation in the EPCORE NHL-1 trial. The validated model was used to further explore a large number of SUD regimens not studied in clinical trials. Based on model predictions, alternative SUD regimens can potentially lead to a small reduction in risk of grade ≥2 CRS. To further assess this, alternative SUD regimens were selected for potential clinical assessment. Conclusions: A dynamic model for CRS was successfully developed, validated, and applied to aid the optimization of an epcoritamab SUD regimen. The model-based optimization of SUD informed and narrowed down the number of doses/cohorts to be tested in clinical trials, simplified study design, and played a critical role in expediting the optimization of the epcoritamab SUD regimen. Citation Format: Tommy Li, Daniel Polhamus, Craig Thalhauser, Apurvasena Parikh, Manish Gupta, Mariana Sacchi, Steven Xu. Simplifying selection and optimization of step-up dosing of subcutaneous Epcoritamab to mitigate CRS risk using repeated time-to-event modeling [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 2798.

Introduction: B-cell lymphoma is a heterogeneous disease with an unmet medical need for efficacious, well tolerated, off-the-shelf therapies that can combine with standard of care (SOC) regimens. Epcoritamab is an IgG1 bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells and enabling killing of target lymphoma cells. Epcoritamab is well suited for combination therapy due to its distinct mechanism of action from that of many SOC regimens that may lead to improved clinical responses. Herein we evaluated the longitudinal pharmacodynamic (PD) effects of epcoritamab in clinical trial patients with diffuse large B-cell lymphoma (DLBCL) treated as monotherapy (EPCORE NHL-1: NCT03625037) and in combination with SOC therapies (EPCORE NHL-2: NCT04663347). Methods: Patients with relapsed/refractory (R/R) DLBCL from EPCORE NHL-1 expansion phase received subcutaneous epcoritamab administered in 28-d cycles. Patients with newly diagnosed or R/R DLBCL from EPCORE NHL-2 received epcoritamab administered with a dosing schedule similar to that in EPCORE NHL-1, in combination with SOC therapies: R-CHOP, R-DHAX/C and GemOx. Biomarkers in fresh whole blood were assessed using validated flow cytometry assays. Cytokine levels in plasma were tested using a validated multiplex immunoassay. Results: Epcoritamab monotherapy induced rapid (within the first cycle), sustained depletion of circulating peripheral B cells (CD19+) in patients with detectable peripheral B cells at baseline. A similar pattern of peripheral B-cell depletion was observed for epcoritamab in combination with SOC. Approximately 24 h following the first full dose, epcoritamab monotherapy induced a moderate but transient elevation of circulating cytokines IFNγ, IL-6 and IL-10. These cytokine patterns were similar for epcoritamab in combination with SOC. Within the first 8 wk of dosing, both epcoritamab monotherapy and in combination with SOC induced a transient elevation of percentages of peripheral CD8+ T cells expressing proliferation (Ki67) and activation (HLA-DR) markers. Expansion of peripheral CD8+ T cells and their effector memory subsets was observed with epcoritamab monotherapy, as well as in combination with SOC in later cycles. Peripheral CD4+ T cells demonstrated patterns similar to most of the biomarker observations in CD8+ T cells with epcoritamab as monotherapy and in combination. Conclusion: These biomarker analyses show that the PD characteristics of epcoritamab monotherapy are maintained overall in combination with SOC therapies containing chemotherapeutic agents with or without rituximab and support the ongoing clinical studies investigating the combination of epcoritamab with SOC therapies in patients with DLBCL. Citation Format: Jimin Zhang, Han Si, Monica Wielgos-Bonvallet, David Soong, Edith Szafer-Glusman, Herve Ghesquieres, Chan Y. Cheah, Lorenzo Falchi, Joshua Brody, Mariana Sacchi, Ali Rana, Brandon Higgs, Brian Elliot, Maria Jure-Kunkel, Christopher W. Chiu. Pharmacodynamic activity of epcoritamab (GEN3013; CD3xCD20) as monotherapy is maintained in combination with standard of care therapies in patients with diffuse large B-cell lymphoma [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 3248.