Abstract PO-003: Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037)
Authors: Monica Wielgos-Bonvallet, Jimin Zhang, Han Si, Kubra Karagoz, Melih Acar, Yasmin Karimi, Herve Ghesquieres, Michael Roost Clausen, Işıl Altıntaş, Binhuan Wang, Wissam Assaily, Matthew Loya, Gregg Masters, Anantharaman Muthuswamy, Brandon Higgs, Mariana Sacchi, Tahi Ahmadi, Mark Fereshteh, Edith Szafer-Glusman, David Soong, Maria Jure-Kunkel, Andrew J Steele
Journal: Blood Cancer Discovery (2024)

Abstract Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, demonstrated deep and durable clinical responses in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We evaluated the correlation of peripheral blood (PB) and tumor tissue biomarkers with clinical response to epcoritamab. Methods: Pts received priming (0.16 mg), intermediate (0.8 mg) and full epcoritamab doses (48 mg). Absolute lymphocyte count (ALC) was analyzed locally. Blood immunophenotyping was assessed by flow cytometry, plasma cytokines by MSD assay, and %CD20+ in tumors by immunohistochemistry (n=117). Gene expression in baseline tumor biopsies was evaluated using HTG EdgeSeq (n=70). Microenvironment scores were estimated from gene expression as a sum of immune (B/T, NK, dendritic, and myeloid cells) and stromal scores (adipocytes, fibroblasts, and endothelial cells). Best overall response as of April 21, 2023 was assessed by independent review committee using Lugano criteria. P values were based on Wilcoxon rank-sum test. Results: In PB at baseline, significantly higher ALC (P=0.031), CD4+ (P=0.0038), and CD8+ (P=0.043) T-cell levels were observed in responders (R) vs nonresponders (NR). Similarly, CD4+ (P=0.02) and CD8+ (P=0.03) signatures and immune and microenvironment scores were higher in baseline tumor tissue in R vs NR. In PB CD8+ T cells, NR showed higher %PD1+ (P=0.016), %TIM3+ (P=0.048), and %TIM3+TIGIT+ (P=0.045). High tumor %CD20+ (≥90%) was observed in most pts (n=97/117); lower %CD20+ (&amp;lt;50%) was observed only in 6 NRs and 1 R. Epcoritamab treatment caused a rapid decline in circulating B cells irrespective of clinical response. Transient reductions in PB CD4+ and CD8+ T cells (ie, margination) were observed within 24 hours (H) after each dose during cycle (C) 1 and were more pronounced in R vs NR. Magnitude of margination for CD8+ T cells after the priming and intermediate doses was significantly lower in NR (reduced by median 22 &amp; 41%) vs R (57 &amp; 70%), while the difference in CD4+ T cells was not as pronounced in NR vs R, resulting in a substantially lower CD4+/CD8+ ratio in NR vs R. In C1, epcoritamab led to an increase of PB CD4+ and CD8+ T cells expressing activation/proliferation markers, with significantly higher fold change from baseline in R vs NR, especially within 24H post-priming dose. Early cytokine peaks of IFNy and IL-10 were more pronounced 6–24H post-priming dose and 6–14H post-first full dose in complete R vs pts with progressive disease. Epcoritamab also appeared to modulate NK cell numbers (under further investigation). Conclusions: In pts with R/R DLBCL, T-cell abundance and increased margination, activation, proliferation, and modulation of cytokines differed in R vs NR. These findings are consistent with epcoritamab’s mechanism of action and demonstrate the dependency on proper T-cell engagement for clinical benefit. Our findings also revealed differences in the dynamics of CD4+ and CD8+ T-cell margination in R vs NR, warranting further investigation. Previously submitted in part to EHA 2024. Citation Format: Monica Wielgos-Bonvallet, Jimin Zhang, Han Si, Kubra Karagoz, Melih Acar, Yasmin Karimi, Herve Ghesquieres, Michael Roost Clausen, Iş?l Alt?ntaş, Binhuan Wang, Wissam Assaily, Matthew Loya, Gregg Masters, Anantharaman Muthuswamy, Brandon Higgs, Mariana Sacchi, Tahi Ahmadi, Mark Fereshteh, Edith Szafer-Glusman, David Soong, Maria Jure-Kunkel, Andrew J Steele. Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037) [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-003.