Response‐adapted mosunetuzumab for untreated follicular and marginal zone lymphomas: significant monotherapy activity seen in results of an interim efficacy analysis

Introduction: Mosunetuzumab (mosun) is a CD3:CD20 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. We hypothesized that mosun would be even more active in patients (pts) without prior lymphotoxic therapy. Therefore, we designed a response adapted study for pts with untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: This is a single center, open label, investigator initiated clinical trial in untreated pts with FL or MZL with indication for treatment. Pts received subcutaneous mosunetuzumab monotherapy for 8 cycles (21 day cycle, Part A) employing step up dosing in cycle 1 (5 mg, 45 mg, 45 mg). A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. Pts with SD or PR could receive 6 cycles (21 day cycle, Part B) of polatuzumab vedotin and obinutuzumab, followed by an end of treatment (EOT) PET/CT. Total planned accrual is 42 pts. The primary endpoint is complete response (CR) rate. A pre-planned interim efficacy analysis is being performed after 20 enrolled pts. If 14 or fewer of the first 20 subjects do not achieve an objective response, the study will be suspended to enrollment. Results: 20 pts enrolled on study between March 24, 2022, and March 11, 2023, and as of the submission date 17 pts are evaluable for safety, and 15 pts are evaluable for efficacy. Patient characteristics are listed in the table. All treatment was delivered as an outpatient. Two pts experienced SAEs (one pt with G3 lung infection followed by G3 shingles, and one pt observed overnight with G1 cytokine release syndrome (CRS). The only other G3 AE observed was diarrhea (1, 6%). Seven (41%) pts experience G1 CRS, with no G2 or higher CRS observed or any grade ICANS observed. No pts required tocilizumab. All CRS events occurred during cycle 1. No heme toxicity greater than Grade 1 was observed (neutropenia 12%, anemia 6%, thrombocytopenia 59%). Three (18%) pts experienced a treatment delay due to G2 hyperglycemia, G2 upper respiratory infection, and G3 pneumonia. No dose modifications were required and all pts have received expected doses of mosun. Nearly all pts (94%) experienced at least one injection site reaction, which were all G1. Since 14/15 (93%) pts so far have achieved an objective response at any time point meeting the interim efficacy threshold, the study is proceeding with total enrollment of up to 42 pts. Among patients who have received all 8 cycles of mosun, 9/11 (82%) have achieved a CR. All pts remain alive and progression-free. Updated data will be presented at the meeting. Conclusion: Mosun is safe and highly active in untreated pts with follicular lymphoma with no G2+ CRS and no ICANS of any grade. The trial met its initial efficacy target allowing full study accrual to proceed. To our knowledge this represents the first presented safety and efficacy data for mosunetuzumab in untreated pts with FL or MZL. The research was funded by a research grant from Genentech Keywords: Combination Therapies, Immunotherapy, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. R. C. Lynch Consultant or advisory role: Cancer Study Group, SeaGen, Foresight Diagnostics Research funding: TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt M. Shadman Consultant or advisory role: Genentech Research funding: Genentech B. G. Till Consultant or advisory role: Mustang Bio, Proteios Technology Research funding: Mustang Bio, BMS Other remuneration: Patent- Mustang Bio S. D. Smith Consultant or advisory role: Genentech, Abbvie Research funding: Genentech C. Ujjani Consultant or advisory role: Genentech A. K. Gopal Consultant or advisory role: Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech, Merck, Karyopharm, Servier, Beigene, Cellectar, Janssen, SeaGen, Epizyme, I-Mab bio, Gilead, Genentech, Lilly, Caribou, Fresenius-Kabi Research funding: Merck, I-Mab bio, IgM Bio, Takeda, Gilead, Astra-Zeneca, Agios, Janssen, BMS, SeaGen, Teva, Genmab Other remuneration: Stock Options: Compliment Corporation