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Abstract Background: Patients (pts) with R/R LBCL often have a poor prognosis. For pts relapsing >1 year after frontline therapy, standard treatment is platinum-based salvage chemotherapy and consolidative autologous stem cell transplant (ASCT). For pts with primary refractory/early relapsing LBCL, chimeric antigen receptor T-cell (CART) therapy is preferred. However, many pts need systemic therapy pre-apheresis given CART approval/production timelines. With universal prior rituximab exposure in pts with R/R LBCL, salvage strategies may be improved by incorporating novel agents instead of rituximab retreatment. We hypothesized mosunetuzumab (Mosun), a CD3xCD20 bispecific T-cell engager active in R/R LBCL (Bartlett et al 2023), can be safely combined with platinum-based chemotherapy and may outperform chemoimmunotherapy with rituximab retreatment. Methods: This is a single center, investigator-initiated phase 1b trial with expansion cohorts enrolling 24 total pts with R/R LBCL after rituximab + anthracycline-based chemotherapy (NCT05464329). Key exclusion criteria are prior ASCT/CART and any history of CNS lymphoma. All pts receive at least 2 cycles of concurrent Mosun + platinum-based chemotherapy, with chemotherapy per treating physician (Arm A: dexamethasone, cytarabine, oxaliplatin [DHAX]; Arm B: ifosfamide, carboplatin, etoposide [ICE]). For all pts, Mosun is administered by IV infusion on 21-day cycles without mandatory hospitalization. For dose level 1 (DL1): in Cycle (C) 1, Mosun is given on Day (D) 1 (1mg), D8 (2mg), and D15 (60mg). In C2+, Mosun is given on D1 only (60mg for C2; 30mg for C3+). Pts receive 20mg IV dexamethasone prior to each C1-C2 Mosun dose, with optional steroid premeds thereafter. DHAX/ICE are given per institutional standards. In the phase 1b portion, pts accrue to each arm independently for 3+3 dose-limiting toxicity (DLT) assessment for Mosun + DHAX/ICE, then the expansion cohort opens for treatment with any chemotherapy that has completed Mosun dose-finding. All pts undergo response assessment by FDG PET-CT post-C2 (PET2). Pts with progressive disease (PD) or inadequate response come off study; others proceed to consolidation per investigator (ASCT/CART) directly or after up to 2 optional additional cycles of Mosun + DHAX/ICE. The primary endpoint is safety; secondary endpoints include ORR, CRR, PFS, and OS. Results: At data cutoff (July 6, 2025), 17 pts have enrolled (Arm A [DHAX]: 10; Arm B [ICE]: 7). Median follow-up is 7 months (range: 0.2-23). Median age was 65 years (range: 47-73). All pts had received 1 prior line of therapy. Seven pts had primary refractory/early relapsing LBCL. One pt withdrew consent pre-C1D8 and was evaluable only for safety but not DLTs or efficacy. No DLTs were observed during the phase 1b portion for either arm, thus DL1 was the recommended Mosun dose irrespective of chemotherapy backbone. Nine pts experienced CRS (all gr1; no tocilizumab required). Serious AEs were gr1 CRS (n=4), gr2 confusion/psychosis (n=4; all attributed to steroids or ifosfamide neurotoxicity), gr3 cholecystitis (n=1), gr3 diverticulitis (n=1), gr3 lower GI bleed (n=1), gr3 thrombosis (n=1), and gr2 RBC transfusion reaction (n=1). Mosun AEs of special interest were gr3 syncope (n=1), gr2 increased bilirubin (n=1), and gr2 increased ALT (n=1). Other notable AEs likely attributable to DHAX/ICE were gr3+ anemia (n=8) and gr3+ thrombocytopenia (n=12). No AEs consistent with ICANS were reported. Two deaths have occurred: sepsis post-ASCT (n=1) and refractory LBCL despite subsequent CART (n=1). Thirteen pts have undergone PET2, with ORR of 12/13 (92.3%) and CR rate of 8/13 (61.5%). Of 12 responding pts, 9 proceeded to ASCT and 1 proceeded to CART consolidation. No pts have progressed post-consolidation. Of 3 pts not proceeding to consolidation post-PET2, one had inadequate PR at PET2, one had PR at PET2 then PD pre-C3 after treatment delay, and one had PD at PET2; all received post-protocol therapy. Median PFS and OS have not been reached. Estimated 12-month PFS is 68% (95%CI: 46-100%) and OS is 76% (95%CI: 51-100%). Conclusions: Mosun + DHAX/ICE demonstrated a manageable safety profile with low-grade CRS. Preliminary efficacy results reveal promising anti-lymphoma activity in a high-risk population, with high CR rate and no progressions after CR with relatively short follow-up. This regimen is encouraging for further study. Long-term efficacy data are awaited to better assess remission durability.