Background: First-line therapy for high-burden FL and MZL includes immunochemotherapy (most commonly rituximab with bendamustine), which is associated with toxicities, is not curative, and leads to a prolonged T-cell depletion. The alternative of rituximab with full-dose lenalidomide did not improve efficacy or toxicity [Morschhauser et al., NEJM 2018]. However, lower-dose, short-course lenalidomide (15mg) may enhance cytotoxic T-cell immunity and efficacy of rituximab [Zucca et al, Blood 2019]. Mosunetuzumab is a CD20xCD3-binding, T-cell-engaging bispecific antibody approved for relapsed/refractory FL after 2 lines of therapy. It results in a complete response (CR) rate of 60% in that setting [Budde et al., Lancet Oncol, 2022], despite prior exposure to immunosuppressive therapies. This trial proposes a novel therapeutic approach to first-line treatment of FL/MZL, exploring 3 hypotheses: 1) that mosunetuzumab will lead to a high rate of CR, and possibly eradication, of FL/MZL when applied before exposure to immunosuppressive modalities; 2) that low-dose lenalidomide can augment the cytotoxic T-cell response when CR is not achieved with mosunetuzumab alone, and 3) that baseline host immune environment measured in treatment-naïve state can predict CR to bispecific antibody therapy. Methods: The Brown University Oncology Research Group BrUOG-401/ML43251 (NCT04792502) is an investigator-initiated, multi-center, single-arm, phase 2 clinical trial for patients (pts) with FL and MZL in need of first-line systemic therapy. Pts with FL must meet the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria of high-burden disease, whereas pts with MZL must require therapy in the investigators’ opinion. As of January 2023, 7 of the planned 52 pts have been enrolled. The trial uses a response-adapted design: pts start with 4 courses of subcutaneous mosunetuzumab monotherapy, using step-up dosing during Cycle 1 (5mg → 45mg → 45mg) to mitigate the risk of cytokine release syndrome (CRS). Pts attaining CR (by Lugano criteria) after Cycle 4 continue for a total of 8 cycles of mosunetuzumab monotherapy. Pts attaining partial response or stable disease receive 4 additional cycles of mosunetuzumab with low-dose lenalidomide augmentation (10mg daily), with further 4 cycles of mosunetuzumab/lenalidomide if CR after C8 is still not attained. The primary endpoints include the ORR and CR rate at final assessment, and rates of toxicities, particularly CRS, tumor flare, and immune-mediated events. PFS and rate of progression of disease at 24 months (POD24) are among secondary endpoints. The study uses Simon’s two-stage design, with the null hypothesis that the CR rate is 53% (based on prior RELEVANCE trial). Correlative studies aim at determining predictive biomarkers of response, including immune signatures and dynamics of circulating tumor DNA during study therapy. Clinical trial information: NCT04792502.