Fixed-Duration Subcutaneous Mosunetuzumab Is Active and Has a Manageable Safety Profile in Patients with Previously Untreated, Low-Tumor Burden Follicular Lymphoma: Updated Results from the Phase II Morningsun Study

Background: Mosunetuzumab (Mosun), a CD20xCD3 bispecific antibody, received accelerated approval for the intravenous treatment of patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) who have received ≥2 prior lines of systemic therapy. Mosun can be administered in the outpatient setting with a fixed treatment duration. In an ongoing Phase I/II study, Mosun administered subcutaneously (SC) induced durable responses with a manageable safety profile in pts with previously untreated low-tumor burden FL (LTB; Flinn et al. ASH 2023). Efficacy, safety and pharmacodynamic profiles of Mosun SC are being evaluated in an open-label, multicenter, Phase II study (MorningSun; NCT05207670) in pts with B-cell non-Hodgkin lymphomas, including previously untreated FL. Here we present >8-month follow-up efficacy, safety and biomarker data for Mosun SC in first-line, LTB FL.

Methods: Pts had untreated Grade (Gr) 1 or 2 FL, LTB by Groupe d'Etude des Lymphomes Folliculaires criteria, Ann Arbor stage III/IV disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Mosun SC injection was administered with step-up dosing in Cycle (C) 1 (Day [D] 1, 5mg; D8, 45mg; D15, 45mg), then 45mg on D1 of each 21-day cycle. Hospitalization was not mandatory. Pts with a complete metabolic response (CMR) after C8 could complete therapy. Pts with a partial metabolic response (PMR) or stable disease continued treatment for up to 17 cycles. Dexamethasone premedication was mandatory in C1 and C2 and optional thereafter. The primary endpoint was progression-free survival at 24 months. Exploratory analyses assessed cytokine levels in pts with versus without cytokine release syndrome (CRS) and pharmacodynamic changes in T and B cells in a subgroup of pts.

Results: As of February 7, 2024, 65 pts were enrolled in US community (n=41) and academic (n=24) centers. At baseline, median age was 63 years (range: 34-82). Most pts had an ECOG PS of 0 (83.1%) or 1 (15.4%); 29 pts (44.6%) had extranodal involvement and 3 pts (4.6%) had B symptoms. Median duration of follow-up was 8.6 months (95% confidence interval [CI]: 5.7-10.9). Median number of cycles was 8 (range: 1-17). Among 60 pts with ≥1 post-baseline tumor assessment, the objective response rate was 95.0% (95% CI: 86.1-99.0; n=57) and CMR was 83.3% (95% CI: 71.5-91.7; n=50). Median time to response was 2.8 months (range: 2.3-8.3). At data cut-off, responses were ongoing in 48 pts with a CMR and in 5 pts with a PMR. In 64 safety-evaluable pts, the most common adverse event (AE) was injection-site reaction (70.3%; Gr 1, 65.6%; Gr 2, 4.7%). CRS by ASTCT occurred in 30 pts (46.9%; Gr 1, 39.1%; Gr 2, 7.8%); CRS events presented early in C1 (53.1%; Gr1, 45.3%; Gr2, 7.8%) and C2 (Gr1, 1.6%). Nineteen pts received CRS treatment (tocilizumab, 7.8%; steroids, 7.8%; tocilizumab + steroids, 4.7%; fluids, 3.1%; low-flow oxygen, 1.6%); 8 pts had a serious AE and were hospitalized. All CRS events resolved. Other common AEs included headache (45.3%; Gr 1, 29.7%; Gr 2, 15.6%), fatigue (45.3%; Gr 1, 35.9%; Gr 2, 9.4%), maculo-papular rash (31.3%; Gr 1, 14.1%; Gr 2, 15.6%; Gr 3, 1.6%), and increased alanine aminotransferase (28.1%; Gr 1, 21.9%; Gr 2, 4.7%; Gr 3, 1.6%). Gr 3/4 AEs in ≥5% of pts were neutropenia without fever (12.5%; Gr 3, 4.7%; Gr 4, 7.8%) and lymphopenia (7.8%; Gr 3, 1.6%; Gr 4, 6.3%). Suspected immune effector cell-associated neurotoxicity syndrome occurred in 2 pts (confusional state, Gr 1, n=1; Gr 2, n=1); all events resolved. Infections occurred in 30 pts (46.9%; Gr 1, 7.8%; Gr 2, 31.3%; Gr 3, 7.8%) with the most common (≥10%) being COVID-19 (17.2%; Gr 1, 7.8%; Gr 2, 7.8%; Gr 3, 1.6%) and upper respiratory tract infections (12.5%; Gr 1, 3.1%; Gr 2, 9.4%). One pt had a Gr 5 (fatal) AE 13.7 months after treatment was completed (reported as unrelated to Mosun; cause unknown). After the first Mosun dose, cytokine levels significantly increased on C1D2 (interleukin-6, n=44, p≤0.001; interferon-γ and tumor necrosis factor-α, n=41, p≤0.001). This spike in cytokine levels did not differ in pts with (n=19) versus without (n=25) CRS events in C1.

Conclusions: Mosun SC monotherapy shows encouraging high efficacy as a fixed-duration treatment in first-line LTB FL. A manageable safety profile was reported, supporting ease of access for patients with drug administration in outpatient settings. Longer follow-up is needed to confirm long-term durability of response and safety.

Burke:Regeneron: Consultancy; Bristol Myers Squibb: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Kymera: Consultancy; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Genmab: Consultancy; Foresight Diagnostics: Consultancy; Nurix: Consultancy; Adaptive Biotechnologies: Consultancy; SeaGen: Consultancy; Eli Lilly and Company: Honoraria, Other: Food/Beverage . Flinn:Portola Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Step Pharma: Research Funding; Tessa Therapeutics: Research Funding; TG Therapeutics: Research Funding; Vincerx Pharma, 2seventybio: Research Funding; Vincerx Advisory Committee: Membership on an entity's Board of Directors or advisory committees; Tennessee Oncology & OneOncology: Current Employment; Pharmacyclics: Research Funding; Pfizer: Research Funding; Myeloid Therapeutics: Research Funding; MorphoSys: Research Funding; Millennium Pharmaceuticals: Research Funding; Merck: Research Funding; Marker Therapeutics: Research Funding; Agios: Research Funding; Acerta: Research Funding; Vincerx: Consultancy; Roche: Consultancy; Kite, a Gilead Company: Consultancy; Novartis: Research Funding; Loxo: Research Funding; Nurix: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Incyte: Research Funding; IGM Biosciences: Research Funding; InnoCare Pharma: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Epizyme: Research Funding; Biopharma: Research Funding; CTI: Research Funding; Curis: Research Funding; Constellation Pharmaceuticals: Research Funding; City of Hope Medical Center: Research Funding; Celgene: Research Funding; CALGB: Research Funding; CALIBR: Research Funding; BMS: Research Funding; BioPath: Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; Genmab: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Budde:AstraZeneca, Mustang Therapeutics, Merck: Research Funding; ADC Therapeutics, AstraZeneca, AbbiVe, Roche, Genentech, Genmab, Jenssen, Regeneron: Consultancy; AstraZeneca, Mustang Therapeutics, Merck: Research Funding; ADC Therapeutics, AstraZeneca, AbbVie, F. Hoffmann-La Roche Ltd, Genentech, Inc., Genmab, Jenssen, Regeneron: Consultancy; City of Hope National Medical Center: Current Employment. Tun:The University of Kansas: Current Employment. Liu:Alaska Oncology & Hematology, LLC: Current Employment; Lilly, Bristol Myer, Pfizer: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd, Bristol Myer, Lilly, Genmab, Novartis, Pfizer, Gilead: Research Funding. Biondo:F. Hoffmann-La Roche Ltd.: Current equity holder in private company, Honoraria; Genentech, Inc.: Current Employment. Jani:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Other: Long term incentives given as RSUs through Genentech / Roche. Wu:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Mun:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Chopra:F. Hoffmann-La Roche Ltd.: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Grindheim:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Farinella:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Villasboas Bisneto:Genentech: Research Funding; Regeneron: Research Funding; Epizyme: Research Funding; Enterome: Research Funding; CRISPR: Research Funding; Aptose: Research Funding.

All study therapy constituted investigational or off-label use. Mosunetuzumab is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.