Background: Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) has shown a significant progression-free survival benefit versus R-CHOP as first line (1L) therapy for DLBCL (Tilly et al. 2022). Glofitamab is a bispecific antibody with a novel 2:1 (CD20:CD3) format; bivalency for CD20 on B cells enables combination with anti-CD20 antibodies, including rituximab. Glofitamab monotherapy induced durable responses in patients (pts) with relapsed/refractory DLBCL and its incorporation in the 1L setting may further improve outcomes (Dickinson et al. 2022). We present results from the expansion stage of an ongoing Phase Ib study (NCT03467373) of glofitamab (Glofit) + Pola-R-CHP in pts with 1L DLBCL. Methods: Pts received Pola-R-CHP on Day (D) 1 of each 21-day cycle (C; max. 6 cycles) and glofitamab in C2‒C6 (C2 step-up dosing [2.5mg C2D8, 10mg C2D15]; target dose [30mg] C3D8 and onwards). Response was assessed by PET-CT using Lugano criteria (Cheson et al. 2014). Efficacy-evaluable pts were those that reached end of treatment (EOT), progressed or died by data cut-off (EOT population). Cytokine release syndrome (CRS) events were graded by ASTCT criteria (Lee et al. 2019) and other adverse events (AEs) by CTCAE (v4.0). Results: As of Nov 14, 2022, 24 pts had enrolled and received study treatment (safety population). Median age was 65 years (range: 32–85), 96% of pts had stage III–IV disease and median IPI score was 3 (IPI 1: 4% [1/24], IPI 2: 33% [8/24], IPI 3: 38% [9/24], IPI 4: 25% [6/24]). Of 24 pts, 17 were efficacy evaluable. After a median follow up of 5.1 (range: 3–8) months, complete metabolic response rate was 76.5% (13/17) and overall response rate was 100% in the EOT population (best overall response). In safety-evaluable pts, Grade (Gr) ≥3 AEs occurred in 15 (63%) pts and Gr ≥3 AEs related to glofitamab in 9 (38%) pts. One Gr 5 AE was reported (acute respiratory distress syndrome, unrelated to study treatment). Serious AEs (SAEs) were reported in 12 (50%) pts and SAEs related to glofitamab in 4 (17%) pts. AEs leading to glofitamab dose interruption occurred in 5 (21%) pts; median dose intensity was 100% for all Glofit + Pola-R-CHP components. Only Gr 1 CRS (n = 3, 13%) was reported, with no treatment or hospitalization required. Neurological AEs (NAEs) occurred in 11 (46%) pts and were mostly Gr 1/2 (10 pts, 42%); one patient had a Gr 3 NAE (hypomania). No NAEs potentially consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 12 (50%) pts (Gr 3, n = 6; Gr 4, n = 6), febrile neutropenia in 2 (8.3%) pts and Gr 3/4 infection in 4 (17%) pts (Gr 3, n = 2; Gr 4, n = 2). Conclusions: Early data suggest that Glofit + Pola-R-CHP has promising efficacy and a similar safety profile to Pola-R-CHP and Glofit + R-CHOP for 1L DLBCL treatment. Glofit + Pola-R-CHP dose intensity was maintained in all pts. Updated data will be presented. Clinical trial information: NCT03467373.