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Better treatment options for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) are needed. Epcoritamab is a subcutaneous CD3xCD20 bispecific antibody with preliminary potent antitumor activity. We report primary results from the LBCL expansion cohort for epcoritamab in patients with R/R B-cell NHL (EPCORE NHL-1; NCT03625037). Adults with R/R CD20+ LBCL were included. Patients had DLBCL (including double/triple-hit and transformed), HGBCL, PMBCL, or FL grade (G) 3B. As of January 31, 2022, 157 patients were treated. Patients received epcoritamab (priming and intermediate doses followed by 48 mg) as 1-mL subcutaneous injections [QW, cycle (C) 1-3; Q2W, C4-9; Q4W, C ≥10] until disease progression or unacceptable toxicity. Patients had a median of 3 (range, 2-11) prior lines of therapy (LOT), 61 (38.9%) received prior CAR T, 61% had primary refractory disease, and 83% were refractory to the last LOT. With a median follow-up of 10.7 mo, ORR by IRC (Lugano/PET-CT) was 63% with 39% complete response (CR). ORR/CR rates were 69%/42% for CAR T-naive patients and 54%/34% for CAR T-exposed patients. Median duration of response was 12 mo and not reached among complete responders. ORR was similar across prespecified subgroups of age, prior LOT, and de novo or transformed disease. The most common treatment-emergent AEs were CRS (49.7%; 31.8% G1, 15.3% G2, 2.5% G3), pyrexia (23.6%), fatigue (22.9%), neutropenia (21.7%), and diarrhea (20.4%). Ten patients (6.4%) experienced ICANS; all but one event was G1-2, and the G5 ICANS was the only treatment-related death. Epcoritamab is a convenient, subcutaneous therapy that demonstrated clinically meaningful, compelling efficacy including deep and durable responses in a challenging-to-treat, highly refractory LBCL population. Efficacy was observed in both CAR T-exposed and CAR T-naive patients. The safety profile was manageable and consistent with previous findings. Funding: This study was funded by Genmab A/S and AbbVie. Encore statement: This abstract was accepted to the European Hematology Association Annual Congress; June 9-17, 2022; Vienna, Austria, and virtual. [ABSTRACT FROM AUTHOR]