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.