Background: Current standard of care for pts with R/R DLBCL eligible for ASCT includes salvage immunochemotherapy, such as rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C), followed by consolidation with high-dose therapy (HDT) and ASCT. However, salvage therapy fails in many pts, and novel treatment (Tx) options are needed to improve response and long-term outcomes. Epcoritamab, a bispecific antibody targeting CD3 on T cells and CD20 on B cells, had a manageable safety profile and meaningful single-agent antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the dose-escalation part of the EPCORE NHL-1 trial. Here we present initial results from arm 4 (epcoritamab + R-DHAX/C) of the EPCORE NHL-2 phase 1/2 trial (NCT04663347). Methods: Adults with R/R CD20⁺ DLBCL who were eligible for HDT-ASCT were enrolled. Pts received standard R-DHAX/C with subcutaneous epcoritamab (QW, 21-d cycle [C] 1–3). If HDT-ASCT was postponed, pts could continue epcoritamab monotherapy (28-d C: QW, C4; Q2W, C5–9; Q4W, C≥10) until disease progression or unacceptable toxicity. Step-up epcoritamab dosing and corticosteroids were required to mitigate CRS in C1. Response was determined by PET-CT per Lugano criteria. Results: As of Jan 26, 2022, 27 pts (median age, 59 y; range, 30–75) had received epcoritamab + R-DHAX/C. Of these, 74% had received 1 prior line of therapy, the remainder (26%) 2–3 prior therapies; 3 pts had prior CAR T. The majority of pts (70%) had primary refractory disease. The most common Tx-emergent adverse events (any grade [G]) were thrombocytopenia (67%), neutropenia (48%; febrile neutropenia, 19% in all pts), infections (37%), nausea (37%), and anemia (33%). Adverse events of special interest were CRS in 8 pts (30%; all G1/2) and ICANS in 1 pt (G2; discontinued epcoritamab, pt with prior CAR T). No clinical tumor lysis syndrome was observed. CRS events occurred early in Tx; median time to resolution was 2 d. Of the 23 evaluable pts, 11 pts underwent ASCT; among these, overall response rate (ORR) was 100% prior to ASCT (82% [9/11] complete metabolic response [CMR]; 18% [2/11] partial metabolic response [PMR]). In 12 pts, HDT-ASCT was postponed/canceled and epcoritamab monotherapy continued; of these, 5 (42%, including 2 with prior CAR T) had CMR and 3 (25%) had PMR. The CMR and PMR rates for the entire evaluable population were 61% (14/23) and 22% (5/23), respectively. Conclusions: Subcutaneous epcoritamab in combination with R-DHAX/C in pts with R/R DLBCL had a manageable safety profile. CRS events were of low grade and resolved with standard management. ORR and CMR rate were high. At the time of data cutoff, 70% of pts had either received ASCT or continued epcoritamab Tx in CMR. Clinical trial information: NCT04663347.