7046 Background: Treating relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is challenging despite advances. AZD0486, a novel IgG4 fully human CD19xCD3 bispecific T-cell engager, showed promising safety and efficacy in patients (pts) with heavily pretreated follicular lymphoma with an overall response rate (ORR) and complete response (CR) rate of 95% and 85%, respectively, at target doses (TD) ≥2.4 mg (Hou JZ, et al. Blood. 2024). We present results from an ongoing phase 1 trial in pts with R/R DLBCL (NCT04594642). Methods: Eligible pts with R/R CD19+ B-cell lymphoma and ≥2 prior lines of therapy (pLOT) received fixed-duration AZD0486 intravenously for 2 years. Initially, pts received either no or 1 step-up dose (SUD). Subsequently, 2SUD on D1/D8 was implemented with TD on D15. TDs were given every 2 weeks in 28-day cycles. After 2 consecutive CRs, pts could receive dosing every 4 weeks. Primary objectives are safety, tolerability, pharmacokinetics, and determining the maximum tolerated dose (MTD). RECIL-based response assessment is performed by central imaging review. Measurable residual disease (MRD) in plasma ctDNA is assessed by PhasED-seq CLARITY assay. CTCAE v5.0 and ASTCT criteria are used to grade adverse events (AEs). Results: As of Sept 29, 2024, 70 pts with R/R DLBCL received AZD0486 at TDs ≤0.8 mg (n=2), 2.4 mg (n=18), 7.2 mg (n=22), 15 mg (n=25), and 25 mg (n=3). Median pLOT was 3 (range, 1–12) and 34 (49%) pts received prior CD19-directed CAR-T therapy. In 61 evaluable pts who received TDs ≥2.4 mg, ORR and CR rate were 46% and 33%, respectively. ORR/CR rates tended to be higher with higher doses (39%/22% at 2.4 mg, 43%/33% at 7.2 mg, and 55%/41% at 15 mg, respectively). ORR/CR rates were higher in pts without prior CAR-T vs CAR-T–exposed pts (57%/39% vs 36%/27%). For pts who received 7.2 mg or 15 mg (median follow-up 8.8 months and 5.3 months, respectively), median duration of response (DOR) was not reached; 12-mo estimated DOR was 64%. One pt who achieved CR progressed. Of the 15 pts who achieved CR and were evaluable for MRD in the 7.2-mg and 15-mg cohorts, 87% (13/15) achieved undetectable MRD. In the overall population (N=70), infections occurred in 37% of pts, with 9% grade [G] ≥3; COVID-19 occurred in 13% of pts. Febrile neutropenia occurred in 3% of pts. Neutropenia ≥G3 occurred in 23% of pts, while anemia ≥G3 occurred in 14%. In pts who received 2SUD (n=54), CRS occurred in 44% of pts, all low grade (G1/G2, 41%/4%), and 20% received tocilizumab; ICANS occurred in 17% of pts (G3, 3%). All CRS and ICANS events in the 2SUD cohort occurred in C1 (except for 1 CRS event on C2D1), were transient, and did not require treatment discontinuation. No AZD0486-related deaths or AEs leading to discontinuation occurred. Conclusions: AZD0486 at TDs ≥2.4 mg showed promising efficacy and manageable safety in pts with R/R DLBCL. Target doses up to 25 mg have been tested without exceeding MTD. Dose escalation is ongoing. Clinical trial information: NCT04594642 .