TPS7093 Background: Approximately 30–40% of patients (pts) with high-risk, aggressive B-NHL are refractory to or relapse after first-line chemoimmunotherapy. Although autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapies are available in the second line, access, eligibility, tolerability, and cost pose limitations for pts, and there remains a need for well-tolerated, effective off-the-shelf therapies in this setting. Odronextamab, a CD20×CD3 bispecific antibody, demonstrated encouraging clinical activity (complete response CR rate 31.5%; median duration of CR 17.9 months) and a generally manageable safety profile as monotherapy in pts with heavily pretreated R/R diffuse large B-cell lymphoma (DLBCL) in the Phase 2 ELM-2 study (Ayyappan, et al. ASH 2023). This study will evaluate odronextamab versus SOC treatment in pts with DLBCL who have relapsed early (within 1 year) or were refractory to first-line therapy. Methods: OLYMPIA-4 (EudraCT 2022-502783-21-00) is a Phase 3, randomized, open-label, multicenter study of odronextamab versus SOC in pts with previously treated aggressive B-NHL. Odronextamab will be administered intravenously in 21-day cycles, with step-up dosing during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, at 160 mg on Days 1, 8, and 15 of C2–4, then as maintenance at 320 mg Q2W until one year from the start of treatment, progressive disease, or death. Treatment in the SOC arm consists of physician’s choice of salvage therapy with intent to proceed to ASCT. SOC regimens are: ifosfamide, carboplatin, and etoposide (ICE); dexamethasone, cisplatin, and cytarabine (DHAP); or gemcitabine, dexamethasone, and cisplatin (GDP), ± rituximab. Pts will receive up to three 21-day cycles of salvage therapy, followed by ASCT. Pts without an optimal response to salvage therapy or ASCT may cross over to receive one year of odronextamab treatment. Key inclusion criteria: ≥18 years of age; aggressive B-NHL that is primary refractory or relapsed within one year of first-line treatment initiation; intent to proceed to ASCT; measurable disease; ECOG performance status 0–1; and adequate organ and hematologic function. Pts with central nervous system lymphoma or active infection are excluded. The primary endpoint is event-free survival, as assessed by independent central review. Key secondary endpoints are progression-free survival, best overall response, and change from baseline in physical function, as measured by EORTC QLQ-C30. Other secondary endpoints include CR rate, duration of response, overall survival, minimal residual disease, pharmacokinetics, and incidence and severity of treatment-emergent adverse events. The trial is currently recruiting and is expected to enroll ~216 pts at ~200 global sites. Clinical trial information: 2022-502783-21-00.