Background: Aggressive non-Hodgkin lymphomas (aNHL) are a diverse group of neoplasms, of which diffuse large B-cell lymphoma (DLBCL) is the most common subtype (Thandra, 2021). Patients (pts) with relapsed/refractory (R/R) DLBCL after one prior therapy who are unable to receive, or relapse after an autologous stem cell transplant (ASCT) and/or chimeric antigen receptor T-cell therapy have a poor prognosis (Salles, 2019; Di Blasi, 2022). Mosunetuzumab (Mosun) is an off-the-shelf CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells (Sun, 2015), with promising efficacy and safety as a single agent, as shown in a Phase I trial in pts with B-cell NHL, including aNHL (Budde, 2022). Mosun has also shown promising safety and efficacy in combination with polatuzumab vedotin (Pola), a CD79b targeted antibody-drug conjugate that delivers the microtubule-disrupting agent monomethyl auristatin E directly to B cells (Dornan, 2009), in a Phase Ib/II trial in pts with R/R aNHL (Budde, ASH 2021). Methods: SUNMO (NCT05171647) is a randomized, open-label, global Phase III trial evaluating the efficacy and safety of subcutaneous Mosun + intravenous (IV) Pola (M-Pola) vs IV rituximab + gemcitabine and oxaliplatin (R-GemOx) in pts with R/R aNHL. Eligible pts have CD20-positive R/R aNHL (DLBCL not otherwise specified [NOS], high-grade B-cell lymphoma double/triple hit or NOS, transformed follicular lymphoma [trFL], or Grade 3B FL), ECOG performance status 0–2, and ≥1 prior systemic therapy (if only one prior line of therapy, pts must be ineligible for ASCT). Exclusion criteria include prior treatment with CD20-directed bispecific antibodies, R-GemOx, or GemOx; prior allogeneic stem cell transplant; and any central nervous system involvement of lymphoma. Pts will be randomized 2:1, stratified by the number of prior lines of therapy (1 vs > 1) and response to last therapy (relapsed vs refractory) to receive M-Pola or R-GemOx IV for a fixed duration of up to 8 cycles (6 cycles for Pola; M-Pola, 21-day cycles; R-GemOx, 14-day cycles). The primary endpoint is progression-free survival (PFS) determined by an independent review facility (IRF). Secondary endpoints include overall survival; IRF- and investigator (INV)-assessed complete response (CR) rate, objective response rate, and duration of response/CR; INV-assessed PFS; patient-reported outcomes; and safety. Biomarker analyses include pre-specified prognostic subsets from baseline biopsies and circulating tumor DNA at baseline and during treatment. Enrollment is ongoing, and an estimated 75 sites globally will enroll approximately 222 pts (M-Pola, 148 pts; R-GemOx, 74 pts). Clinical trial information: NCT05171647.