Background: In pts with newly diagnosed DLBCL, standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has a 5-year progression-free survival (PFS) rate of 67.0%, 58.4%, and 45.8% for International Prognostic Index (IPI) 2, 3, and 4–5, respectively (Ruppert et al, Blood 2020). Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell–mediated killing of malignant CD20+ B cells (Hutchings et al, Lancet 2021). Epcoritamab monotherapy demonstrated deep and durable responses (overall response rate [ORR], 63%; complete response rate, 39%) and was generally well tolerated in pts with relapsed/refractory (R/R) aggressive, large B-cell lymphoma (LBCL) (Thieblemont et al, J Clin Oncol 2022). Results from an ongoing phase 1/2 study in high-risk pts with newly diagnosed DLBCL (EPCORE NHL-2 arm 1; NCT04663347) show that epcoritamab + R-CHOP has promising efficacy and a manageable safety profile in high-risk pts with IPI 3–5. Among efficacy-evaluable pts (n = 31), ORR was 100% and complete metabolic response (CMR) was 77%; cytokine release syndrome (CRS) events (n = 17/33; 52%) were mostly low-grade, had predictable timing, and did not lead to treatment discontinuation (Falchi et al, ASCO 2022, abstract 7523). These encouraging data support further evaluation of epcoritamab + R-CHOP for the treatment of newly diagnosed DLBCL. Methods: This phase 3, global, multicenter, open-label study (NCT05578976) evaluates the efficacy and safety of epcoritamab + R-CHOP in adults newly diagnosed with one of the following CD20+ DLBCL (de novo or transformed from follicular lymphoma [FL]): 1) DLBCL, not otherwise specified (NOS); 2) high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; 3) T-cell/histiocyte–rich LBCL; 4) Epstein-Barr virus–positive DLBCL, NOS; or 5) FL grade 3b. Other key eligibility criteria include IPI ≥2 (pts with IPI 2 not to exceed ~30% of total pts), ECOG PS 0–2, and ≥1 measurable disease site. Approximately 900 pts will be randomized 2:1 to either epcoritamab + R-CHOP (6 cycles, followed by 2 cycles of epcoritamab) or R-CHOP (6 cycles, followed by 2 cycles of rituximab). The primary efficacy endpoint is PFS in pts with IPI 3–5 (based on IRC assessment per Lugano criteria). The secondary efficacy endpoints are PFS in pts with IPI 2–5, event-free survival, CMR, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (CRS, immune cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome. Enrollment began in January 2023 globally. Clinical trial information: NCT04663347, NCT05578976.