Subcutaneous Mosunetuzumab Is Active with a Manageable Safety Profile in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphomas (B-NHLs): Updated Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Bi-mAb) that redirects T cells to eliminate malignant B cells, is the first Bi-mAb approved for R/R follicular lymphoma (FL; EMA 2022; Budde et al. Lancet Oncol 2022) and can be administered intravenously in the outpatient setting with a fixed treatment duration. A subcutaneous (SC) formulation that aims to improve safety and convenience is under evaluation. We present results for SC Mosun in a larger population with longer follow-up than previously reported (Bartlett et al. ASH 2021).

Methods: GO29781 is a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with R/R B-NHL (NCT02500407). Pts with ≥1 prior line of systemic therapy (dose-escalation) or ≥2 prior lines (dose-expansion) were included. SC Mosun was administered with step-up dosing in Cycle (C) 1, then given on Day (D) 1 of subsequent 21-day cycles. The first 2 dose-escalation groups received Mosun 5mg on C1D1, 15mg or 45mg on C1D8, and 45mg on C1D15 and D1 from C2 onwards (5/15/45mg [Group 1] and 5/45/45mg [Group 2], respectively). A third group received Mosun 5mg on C1D1, 45mg on C1D8, 90mg on C1D15 and C2D1, and 45mg on D1 from C3 onwards (5/45/90/90/45mg [Group 3]). Pts with a complete response (CR) after 8 cycles completed therapy; pts with a partial response or stable disease continued treatment up to 17 cycles. Primary objectives included safety, tolerability and identification of the recommended Phase II dose.

Results: At data cut-off (May 20, 2022) 89 pts with R/R B-NHL received SC Mosun (Group 1: n=39, Group 2: n=47, Group 3: n=3). Most common histologies were diffuse large B-cell lymphoma (56%), transformed FL (19%) and FL (12%). Median (range) age was 68 years (24-88). Median number of prior systemic therapies was 3; 85.1% and 83.9% of pts were refractory to their last prior therapy or prior anti-CD20 therapy, respectively; 32.6% had received prior CAR T-cell therapy. Median (range) time on study was 9.9 months (m; 0.4-19.7) and cycles completed was 5 (1-17). No dose-limiting toxicities were observed in dose escalation. Most common all-Grade (Gr) adverse events (AEs) were injection-site reaction (62%; all Gr 1/2) and cytokine release syndrome (CRS; 27%; all Gr 1/2). Gr 3/4 and serious AEs were reported in 49% and 45% of pts, respectively. One AE led to Mosun discontinuation (COVID-19; Group 1). Gr 5 AEs were reported in 5 pts; none were considered Mosun-related by investigators (Group 1: n=3 [COVID-19 n=2; large intestine perforation n=1]; Group 2: n=2 [COVID-19 pneumonia and septic shock]). CRS was reported in 15/39 pts (38%), 8/47 pts (17%) and 1/3 pts in Groups 1, 2 and 3, respectively. Most CRS events occurred during C1. Median onset time since prior Mosun and median duration was 2 days (ranges 0-4 and 1-6, respectively). CRS events were low Gr (Gr 1: 18%; Gr 2: 9%; Figures 1 and 2) and all resolved; 2 pts (2%) received corticosteroids and 4 (5%) received tocilizumab for CRS. Neutropenia was reported in 19 pts (21%; Gr 3/4 in 17 [19%]) and febrile neutropenia in 1 pt (1%; Gr 3); median (range) neutropenia duration was 8 days (2-64). Serious infections were reported in 12 (14%) pts (Gr 3/4: n=8; Gr 5: n=4). Treatment-related neurological AEs possibly consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 3 pts (3%; all Gr 1: lethargy, memory impairment, and ICANS [confusion] with Gr 1 CRS); all resolved. Tumor flare was reported in 4 pts (4%; Gr 2: n=2; Gr 3: n=2); all resolved. All pts with indolent NHL (iNHL; all FL; 11/11) and 75/76 pts with aggressive NHL (aNHL) were enrolled ≥3 m prior to cut-off and included in the efficacy analysis. Overall response rate was 82% in iNHL and 36% in aNHL; CR rate was 64% in iNHL and 20% in aNHL, with 18/22 CRs (82%) ongoing at data cut-off. Median duration of response was 6.7 m (95% CI: 4.8-not estimable) in aNHL and not reached in iNHL (9-m event-free rate: 78% [95% CI: 51-100]).

Conclusions: SC Mosun demonstrated single-agent activity similar to the intravenous formulation in pts with R/R B-NHL. SC Mosun with C1 step-up dosing had a manageable safety profile, including low CRS rates across dose schedules. Based on exposure-response considerations regarding tolerability and clinical activity, 5/45/45mg was chosen as the recommended dose. SC Mosun could improve outcomes in R/R B-NHL while increasing convenience and reducing healthcare resource utilization.

Budde:Genentech: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board; Merck: Research Funding; AstraZeneca: Research Funding; Amgen Inc: Research Funding; Ziopharm Oncology Inc: Other: DMSC member for a phase 1 clinical trial. Bartlett:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolos: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Schuster:AbbVie: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Fate Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Genmab: Consultancy; Incyte: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Legend Biotech: Consultancy; Loxo Oncology: Consultancy; Merck: Research Funding; MorphoSys: Consultancy; Mustang Biotech: Consultancy; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmacyclics: Research Funding; Regeneron: Consultancy; Roche: Consultancy, Research Funding; TG Therapeutic: Research Funding. Assouline:Genentech/Roche, Astra Zeneca, Novartis, BMS, Jazz, Gilead, Amgen, Beigene, Abbvie, Paladin: Consultancy, Honoraria; Novartis: Research Funding. Yoon:Amgen: Consultancy; Janssen Pharmaceutical: Consultancy; Astellas Pharma: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Roche-Genetech: Research Funding; Chugai Pharmaceutical: Consultancy; Novartis: Consultancy; Kyowa Kirin: Research Funding; Yuhan Pharmaceutical: Research Funding; Tikaros: Consultancy. Matasar:Epizyme: Consultancy, Honoraria; Merck: Consultancy, Current equity holder in private company; Takeda: Consultancy, Honoraria; Teva: Consultancy; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; IMV Therapeutics: Consultancy, Honoraria; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; ImmunoVaccine Technologies: Honoraria, Research Funding. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dreyling:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly/Loxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Abbvie: Research Funding. Yoon:BMS: Honoraria; Amgen: Honoraria; Roche: Honoraria; Kirin Pharm: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Celltrion: Honoraria, Research Funding; Sanofi: Research Funding; Beigene: Research Funding; Boryung pharmaceutical: Honoraria, Research Funding; SAMYANG Biopharm: Honoraria, Research Funding; Pharos iBio: Consultancy; Ab clone: Consultancy; GI cell: Consultancy; Novartis: Honoraria; Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; GC Cell: Consultancy; AbbVie: Research Funding. Hess:BMS: Honoraria; BeiGene: Honoraria; Takeda: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; MorphoSys: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel grants, Research Funding; Genmab: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; ADC Therapeutics: Consultancy; Abbvie: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Research Funding. Radford:The University of Manchester and Christie Hospital NHS Foundation Trust: Current Employment; ADC Therapeutics: Consultancy, Current equity holder in private company, Current holder of stock options in a privately-held company, Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Kite Pharma: Consultancy; Astrazenca: Current equity holder in private company, Current holder of stock options in a privately-held company. Wiebking:Genentech, Inc.: Current Employment; F. Hoffmann La Roche, Ltd.: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Yin:F. Hoffmann La Roche, Ltd.: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Genentech, Inc.: Current Employment, Patents & Royalties. Cybulski:Roche/Genentech: Current Employment, Current equity holder in publicly-traded company. Turner:GSK: Ended employment in the past 24 months; F. Hoffmann La Roche, Ltd.: Current holder of stock options in a privately-held company; Genentech, Inc.: Current Employment. Huang:F. Hoffmann La Roche, Ltd.: Current Employment. Zhou:FibroGen, Inc.: Ended employment in the past 24 months; F. Hoffmann La Roche, Ltd.: Current Employment. Penuel:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Wei:F. Hoffmann La Roche, Ltd.: Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties; Genentech, Inc.: Current Employment. Sehn:Chugai: Consultancy, Honoraria; Teva, Roche/Genentech: Consultancy, Honoraria, Research Funding; AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Debiopharm, Genmab, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Novartis, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Consultancy; AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Honoraria.

Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent in the United States.