Mosunetuzumab Monotherapy Demonstrates Encouraging Activity and a Manageable Safety Profile in Patients with Heavily Pre-Treated Relapsed or Refractory Mantle Cell Lymphoma

Background: New treatment options are needed for patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially those with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate B cells, including those that cause malignant disease. In a Phase I/II study (NCT02500407), mosunetuzumab demonstrated durable remissions with a manageable safety profile in pts with R/R B-cell non-Hodgkin lymphoma, including those with R/R MCL (Budde et al. J Clin Oncol 2024). Here we report the first efficacy and safety data from an expansion cohort for mosunetuzumab monotherapy at the recommended Phase II dose in pts with MCL who are R/R to BTKi therapy.

Methods: Eligible pts with MCL, R/R to ≥1 prior regimen containing a BTKi, were enrolled. Mosunetuzumab was administered intravenously in 21-day cycles with step-up dosing in Cycle (C)1 (C1 Day [D]1, 1mg; C1D8, 2mg; C1D15/C2D1, 60mg; C3D1 and onwards, 30mg). Hospitalization was not mandatory. Pts with a complete response (CR) by C8 discontinued treatment; those with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoints were safety and tolerability. Efficacy was a secondary endpoint and was assessed by investigators according to Cheson 2007 criteria. Cytokine release syndrome (CRS) events were graded using the ASTCT criteria.

Results: As of May 13, 2024, 25 pts were enrolled. Median age was 70 years (range: 50-89), 92% of pts had Ann Arbor stage III/IV disease, 64% had ECOG performance status 1, and 84% had MCL International Prognostic Index (MIPI) score ≥6. Median number of prior therapies was 3 (range: 2-6). All pts had ≥2 prior therapies, 80% had ≥3 prior therapies; 32% had a prior autologous stem cell transplant; 72% and 96% were refractory to a prior anti-CD20 therapy and a prior BTKi, respectively; 92% were refractory to their most recent regimen. Median number of mosunetuzumab cycles was 5 (range: 1-17), with 3 pts receiving >8 cycles. Median duration of follow-up for overall survival (OS) was 54.5 months.

The best overall response rate (ORR) and CR rate were 44% and 24%, respectively. Median duration of response was 10.3 months (95% confidence interval [CI]: 2.3-19.5); median duration of CR was 18.0 months (95% CI: 10.3-22.3). Median progression-free survival was 3.7 months (95% CI: 1.4-5.8) and median OS was 7.3 months (95% CI: 3.6-25.9). The ORR and CR rate were consistent in pts with MIPI ≥6 (n=21; ORR 43%, CR 24%); additional subgroup efficacy analyses based on Ki-67 proliferation index and blastoid/pleomorphic morphology will be presented.

The most common adverse events (AEs) were CRS (52%), fatigue (36%), and pyrexia (36%). CRS events were predominantly Grade (Gr) 1/2 (48%); Gr 3 CRS occurred in 1 pt; no Gr ≥4 CRS events were reported. CRS events occurred only in C1 and all events resolved. The median duration of CRS was 3 days (range: 1‒7). In pts with CRS, 4 (31%) received tocilizumab. Suspected immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred in 3 pts (Gr 1 confusional state [n=2]; Gr 2 delirium [n=1]); 2 events occurred concurrently with CRS. All events occurred early (C1 and C2) and resolved without steroid use. Gr 3/4 AEs were reported in 19 (76%) pts; Gr 3/4 AEs occurring in ≥10% of pts included neutropenia (28%; no febrile neutropenia), hypophosphatemia (20%), thrombocytopenia (16%), and anemia (12%). Serious AEs (excluding fatal PD) occurred in 14 (56%) pts; 10 (40%) were treatment related. No Gr 5 AEs were reported (excluding PD). An AE leading to treatment discontinuation occurred in 1 pt (subdural haematoma; unrelated to mosunetuzumab).

Conclusions: Fixed-duration mosunetuzumab demonstrated encouraging single-agent activity in a challenging-to-treat population of pts with high-risk and refractory MCL. The safety profile was manageable, characterized by predominantly low-grade CRS events confined to C1, all of which resolved. Mosunetuzumab's tolerability, off-the-shelf availability, lack of mandatory hospitalization, and convenient dosing schedule provide rationale for further exploration in this setting. Currently, mosunetuzumab is being investigated in combination with polatuzumab vedotin for pts with R/R MCL (NCT03671018).

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. Matasar:Kite: Honoraria; IMV Therapeutics: Honoraria; Epizyme: Honoraria; AstraZeneca: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Merck: Current equity holder in publicly-traded company; Genmab: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; GM Biosciences: Consultancy, Research Funding; BMS/Celgene: Honoraria; Allogene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding. Sehn:AbbVie; Amgen; AstraZeneca; Beigene; BMS/Celgene; Genmab; Kite/Gilead; Incyte; Janssen; Merck; Seagen; F. Hoffmann-La Roche Ltd; Genentech, Inc.: Honoraria; AbbVie; Amgen; AstraZeneca; Beigene; BMS/Celgene; Genmab; Kite/Gilead; Incyte; Janssen; Merck; Seagen; F. Hoffmann-La Roche Ltd; Genentech, Inc.: Consultancy; F. Hoffmann-La Roche Ltd; Genentech, Inc.; Teva: Research Funding. Assouline:BeiGene: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; F. Hoffman-La Roche Ltd.: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis Canada Inc.: Research Funding; Ipsen: Consultancy; Gilead: Honoraria; Pfizer: Consultancy. Kuruvilla:F. Hoffmann-La Roche Ltd, AstraZeneca, Merck, Novartis: Research Funding; DSMB Karyopharm: Other; AbbVie, Amgen, AstraZeneca, BMS, Genmab, Gilead, Incyte, Janssen, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Seattle Genetics: Honoraria; AbbVie, BMS, Gilead, Merck, F. Hoffmann-La Roche Ltd, Seattle Genetics: Consultancy. Flinn:Myeloid Therapeutics: Research Funding; Novartis: Research Funding; Nurix: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; 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; MorphoSys: Research Funding; Millennium Pharmaceuticals: Research Funding; Merck: Research Funding; Marker Therapeutics: Research Funding; Loxo: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Infinity Pharmaceuticals: 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; Epizyme: Research Funding; Fate Therapeutics: 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; BMS: Research Funding; CALIBR: Research Funding; BioPath: Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; Agios: Research Funding; Vincerx: Consultancy; Acerta: Research Funding; Roche: Consultancy; Kite, a Gilead Company: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Tennessee Oncology & OneOncology: Current Employment; Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Yoon:Janssen, Novartis, F. Hoffmann-La Roche Ltd, Genentech, Inc.: Consultancy; Janssen: Honoraria; F. Hoffmann-La Roche Ltd, Genentech, Inc.: Research Funding. Bosch:Vall d'Hebron University Hospital (Barcelona, Spain): Current Employment; F. Hoffmann-La Roche Ltd, Novartis, Janssen, AbbVie, Gilead, Mundipharma, Takeda, Celgene/BMS, AstraZeneca, Lilly, BeiGene, TG Therapeutics, Ascentage: Consultancy; F. Hoffmann-La Roche Ltd, Celgene/BMS, Karyopharm, Takeda, AstraZeneca, Novartis, AbbVie, Janssen: Research Funding; F. Hoffmann-La Roche Ltd, Novartis, Janssen, AbbVie, Gilead, Mundipharma, AstraZeneca, Celgene/BMS, Takeda, Ascentage, Lilly, BeiGene: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd, Janssen, AbbVie, Novartis, Celgene, Gilead, Takeda, AstraZeneca, BeiGene, Lilly: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, Novartis, Janssen, AbbVie, Gilead, Mundipharma, Celgene, Takeda, AstraZeneca, Celgene/BMS, BeiGene, Lilly: Other. Greenwald:F. Hoffmann-La Roche Ltd, Genentech, Inc.: Speakers Bureau. Gutierrez:University Hospital of Salamanca: Current Employment; Amgen, Sanofi: Honoraria. Tzachanis:BMS, Veraxa: Consultancy; BMS: Research Funding. Marlton:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene: Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas; Janssen; BeiGene; AstraZeneca; Otsuka; AbbVie; Menarini; Pfizer; MSD; Jazz; Novartis: Membership on an entity's Board of Directors or advisory committees. McGuirt:Genentech, Inc.: Current Employment. Yin:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Patents & Royalties. Wei:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Patents & Royalties. Kwan:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Tracy:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Penuel:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Bartlett:Washington University School of Medicine: Current Employment; Autolus: Research Funding; ADC Therapeutics: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees.

All study therapy constituted investigational or off-label use. Mosunetuzumab (Lunsumio) 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.