Immune Biomarkers of Mechanism of Action of Epcoritamab (Epcor) Plus Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) in Frontline DLBCL

Background: Epcor, a subcutaneous CD3xCD20 bispecific antibody, is approved as monotherapy for adults with relapsed or refractory DLBCL after ≥2 lines of systemic therapy. Combining epcor with antineoplastic agents that have complementary mechanisms of action may offer enhanced clinical benefit to patients. Epcor combined with pola-R-CHP showed manageable safety and high response rates (ORR 100%; CR 88.6%) in newly diagnosed patients with DLBCL from arm 3 of the phase 1b/2 EPCORE NHL-5 (NCT05283720) study (Lavie et al, EHA 2024). Herein we report pharmacodynamic and correlative biomarkers of response, demonstrating that epcor in combination with pola-R-CHP drives deep and durable responses, including MRD negativity in this patient population. Methods: EPCORE NHL-5 is an ongoing, multi-arm, open-label, global study investigating novel, antineoplastic agents in adult participants with non-Hodgkin lymphoma. In arm 3, patients with newly diagnosed CD20+ DLBCL (n=37) were treated with 21-d cycles of epcor with pola-R-CHP until cycle 6, followed by 2 cycles of epcor monotherapy only. Following step-up dosing in cycle 1, the full dose of epcor (48 mg) was given QW during cycles 2-4 and Q3W during cycles 5-8. The following biomarker assessments were performed as per-protocol predefined timepoints: CD20/PAX5 expression in baseline tumor samples assessed by immunohistochemistry (IHC), peripheral blood (PB) immune phenotypes assessed by flow cytometry, and plasma cytokines analyzed by multiplex immunoassay. Plasma ctDNA levels were quantified at various timepoints during treatment using the Avenio NHL CAPP-Seq assay (Roche); MRD negativity was defined as <1 mutant molecule per ml (MMPM). Best overall response (BOR) was assessed by an independent review committee using Lugano criteria reported as of February 29, 2024. Results: IHC assessment of baseline tumor biopsies (n=14) showed a high percentage of CD20+ tumor cells (range: 86.2-98.5% double CD20+ PAX5+ cells) across CR and PR patients tested. While all evaluable patients were responders, with 23 CRs and 4 PRs at the 48 mg epcor dose, proinflammatory and immunomodulatory cytokines including IFN-γ, IL-6, IL-2, and IL-10 peaked after the first full dose of epcor. Cytokine levels were greater in patients achieving CR vs PR (IFN-γ, P=0.02), while only increased levels of IL-6 showed a trend with grade 1-2 CRS vs no CRS (P=0.07, fold change [FC] 5.0 vs 2.2). Immune profiling in baseline PB samples showed a 3.2-fold higher proportion of activated T cells (%CD3+CD69+) and 25.0-fold lower Treg counts (CD4+FoxP3+CD25+) in patients with CR vs patients with PR. CD8+ T-cell counts increased with treatment (~2.4 FC at EOT vs baseline), while median CD4+ T-cell counts did not show a significant change during treatment. T-cell proliferation defined by % Ki67+ cells reached maximum levels at the end of the first cycle and was higher in CD8+ (3.6 FC) vs CD4+ (2.4 FC). Analysis of T-cell subpopulations indicated an increase in the number of CD8+ T-cell effector memory (EM) cells (CD197-CD45RA-) with treatment. Specifically, a progressive and sustained increase in % CD8+ EM cells expressing differentiation and functional markers such as HLA-DR, CD38 (3.2 FC, P=0.0002) and Granzyme B (1.6 FC, P=0.0001) was observed. A sharp reduction in ctDNA levels was observed after the first treatment cycle, with a median FC from baseline at C2D1 of ~347 (P<0.0001). Patients who achieved MRD negativity by C2D1 (n=19) showed higher proportions of baseline CD69+ activated T cells (1.5-fold) and naive CD8+ T cells (8.0 fold) vs patients who were MRD positive at C2D1 (n=7). At C3D1, MRD negativity rates in all evaluable and CR patients were 80% and 85%, respectively, and MRD negativity was sustained during and after treatment in all but 1 of the patients that achieved CR. Additional analyses are ongoing and updated data will be presented. Conclusions: Epcor in combination with pola-R-CHP demonstrates high rates of deep responses, including MRD-negative CR, rapid but transient induction of pro-immunomodulatory cytokines, and sustained activation and expansion of CD8+ EM T cells, supporting their role as key players in mounting an antitumor response. Overall, these data demonstrate that immune activity with Epcor+pola-R-CHP treatment is consistent with the mechanism of action of epcor and contributes to a robust clinical response.