Background: Glofitamab (Glofit) is a CD20xCD3 bispecific antibody which engages and redirects T cells to eliminate B cells. Glofit monotherapy recently received FDA and EMA approval for treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 prior lines of therapy. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that has a complementary mode of action to Glofit, with little toxicity overlap. In this open-label, multicenter Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and a manageable safety profile in patients with R/R DLBCL (Hutchings et al. ICML 2023). We present updated results with longer follow-up in patients with R/R DLBCL, including high-grade B-cell lymphoma (HGBCL), and in patients with prior chimeric antigen receptor (CAR) T-cell therapy. Methods: Patients receivedobinutuzumab 1000mg on Cycle (C) 1 Day (D) 1 to mitigate the risk of severe cytokine release syndrome (CRS). Pola 1.8mg/kg was given on C1D2 and D1 of C2-6 (21-day cycles). Glofit was given with step-up dosing in C1 (C1D8 2.5mg; C1D15 10mg; D1 of C2-12 10/30mg) for up to 12 cycles. The primary objective was to establish the recommended Phase II dose of Glofit when combined with Pola; this was previously identified as 30mg based on the dose-escalation phase and the NCT03075696 study (Hutchings et al. ASH 2021; Hutchings et al. J Clin Oncol 2021). Results: At the data cut-off (Jan 25, 2023), 111 patients had received ≥1 dose of study drug (safety population). The median age was 68 (range 23-82) years; 61.3% of patients were male; 50.5% had DLBCL not otherwise specified (NOS), 24.3% had HGBCL, 23.4% had transformed follicular lymphoma (trFL), and 1.8% had primary mediastinal large B-cell lymphoma (PMBCL). Most patients were refractory to their last prior therapy (71.2%). Median number of prior lines of therapy was 2 (range 1-7; 61.3% of patients had received ≥2), 24.3% had received prior CAR T-cell therapy. The overall response rate (ORR) in 109 efficacy-evaluable patients was 78.0%, with a complete metabolic response (CMR) rate of 56.0%. In patients with DLBCL NOS (n=56), ORR and CMR rate were 85.7% and 60.7%, respectively. In patients with trFL (n=26), ORR and CMR rate were 76.9% and 53.8%, respectively. In patients with HGBCL (n=25), ORR and CMR rate were 60.0% and 44.0%, respectively. The two patients with PMBCL achieved a CMR. In patients who had prior CAR T-cell therapy (n=27), ORR was 77.8% and CMR rate was 44.4%. In 61 patients who had a complete response, estimated 6- and 12-month duration of complete response (DOCR) rates were 89.2% and 73.1%, respectively ( Figure). Estimated 6-month and 12-month DOCR rates in patients with DLBCL NOS (n=34) were 84.2% and 59.2%, respectively; with trFL (n=14), were 92.9% and 85.7%; with HGBCL (n=11), both were 100%. In patients with PMBCL (n=2), the estimated 6-month DOCR was 100%. With a median follow-up of 13.0 months, median progression-free survival was 10.4 (95% confidence interval [CI]: 5.8-19.0) months ( Figure). Median overall survival was not reached after a median survival follow-up of 15.2 months. In 108/111 patients who had received ≥1 dose of Glofit, the most common adverse event (AE) was CRS (45.4% [Grade 1, 30.5%; Grade 2, 13.9%]). One patient had Grade 5 CRS in the context of an unresolved infection; the patient declined further CRS management when the event was Grade 3. Of 111 safety-evaluable patients, 27 (24.3%) had peripheral neuropathy (all Grade 1/2, 8 events were resolved). Glofit-related AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 patients and were all Grade 1/2. Grade 3/4 AEs were reported in 61.3% of patients, with neutropenia the most common event (29.7%). Serious AEs occurred in 58.6% of patients, and Grade 5 AEs occurred in 6.3% of patients (5/7 events due to COVID-19); 9.9% of patients discontinued any treatment due to an AE (6.3% discontinued Pola; 9.0% discontinued Glofit). Conclusions: Glofit+Pola demonstrated high response rates and durable responses in heavily pre-treated patients, the majority of whom were refractory to their last prior therapy, across all histologies, including in patients with HGBCL and those with prior CAR T-cell therapy. The safety profile was manageable and consistent with the individual drugs. The rates of CRS events and AEs potentially consistent with ICANS were low. Updated data will be presented.