Evaluation of pharmacodynamic biomarkers of epcoritamab (GEN3013; CD3×CD20): results from a phase I/II dose-escalation study in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Background B-cell non-Hodgkin lymphoma (B-NHL) is a heterogeneous disease that can be complex to diagnose and treat. There is a continuing need for new therapies for patients with B-NHL whose disease no longer responds to standard of care. Monoclonal antibodies (mAbs) targeting CD20, a B-cell surface protein, are a successful and commonly used therapy; but, in many cases, B-NHL relapses or becomes refractory (R/R) to treatment. Epcoritamab (GEN3013; CD3xCD20) is a novel bispecific antibody that simultaneously binds CD20 on B cells and CD3 on T cells, an essential activating molecule on the T-cell surface, leading to potent T-cell-mediated killing of CD20-expressing cells. Subcutaneously (SC) administered epcoritamab has shown promising single-agent antitumor activity in B-NHL (Lugtenburg et al. ASH 2019 [abstract:121460]). SC administration (in conjunction with step-up dosing) may mitigate cytokine release syndrome (CRS) and related syndromes; compared with intravenous administration, SC epcoritamab was associated with a reduction in peak plasma cytokine levels in cynomolgus monkeys (Engelberts et al. EBioMedicine 2020). Here, we present the results of pharmacodynamic (PD) biomarkers studies from the dose-escalation part of the ongoing first-in-human (FIH) trial in patients with R/R B-NHL (NCT03625037). Aims Exploratory analyses were performed to evaluate biomarkers associated with clinical responses to epcoritamab and PD markers linked to its mechanism of action (MOA). Methods During cohort dose escalation, adults with R/R CD20+ B-NHL, previously treated with anti-CD20 mAb, received a single SC injection of flat-dose epcoritamab in 28-day cycles (q1w: cycle 1–2; q2w: cycle 3–6; q4w thereafter) until disease progression or unacceptable toxicity. The primary objective of the study is to determine the maximum tolerated dose and recommended phase 2 dose. To better understand the MOA of epcoritamab, biomarker analyses were conducted using peripheral blood to evaluate the effects of epcoritamab on circulating immune cells and cytokines using flow cytometry and immunoassays, respectively. Results Epcoritamab induced a rapid and sustained depletion of circulating B cells (if present at baseline after prior anti-CD20 therapy). A transient decrease in peripheral CD4+ and CD8+ T cells was observed within 6 hrs of first dose and subsequent dosing induced expansion of both CD8+ and CD4+ T cells from baseline. Additionally, activation markers CD69 and CD279 were upregulated on CD4+ and CD8+ T cells. Exploratory analysis of biomarkers associated with clinical response indicated a trend for greater expansion of activated and total T cells (both CD8+ and CD4+) and higher IFNγ levels in patients who had a partial or complete response to epcoritamab. Step-up dosing and SC administration of epcoritamab during dose escalation were implemented to mitigate CRS. CRS occurred in 59% of patients dosed to date: all Grade 1/2; all resolved. Moderate IL-6 and TNF elevations were observed with median peak cytokine levels of <400 pg/mL and <50 pg/mL, respectively. These PD biomarker changes in T cells and cytokines were consistently observed across different histologies. Additional biomarker analyses are ongoing and updated data will be presented. Conclusion The PD biomarker data from this FIH trial of epcoritamab are consistent with the clinical activity of epcoritamab for the treatment of B-NHL.