Subcutaneous (SC) Administration of Mosunetuzumab with Cycle 1 Step-up Dosing Is Tolerable and Active in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphomas (R/R B-NHL): Initial Results from a Phase I/II Study
Authors: Bartlett Nancy L. , Giri Pratyush , Budde L. Elizabeth , Schuster Stephen J. , Assouline Sarit , Matasar Matthew J. , Yoon Sung-Soo , Canales Miguel , Gutierrez Norma C. , Fay Keith , Cheah Chan-Yoon , Marlton Paula , Wiebking Volker , Yin Shen , To Iris , Li Chi-Chung , Huang Huang , Zhou Mingzhu , Penuel Elicia , O'Hear Carol , Sehn Laurie H. 
Published: November 2021

Abstract
Background: Cytokine release syndrome (CRS) is a potentially serious complication of T-cell engaging immunotherapy. Effective measures are needed to reduce the rate and severity. In a multicenter Phase I/II study (NCT02500407), the CD20xCD3 bispecific antibody mosunetuzumab (Mosun) showed durable complete responses (CR) and had manageable safety in patients (pts) with late-line R/R B-NHL (Schuster et al. ASH 2019). IV administration with Cycle (C) 1 step-up dosing was an effective strategy for mitigating CRS during C1 (Bartlett et al. ASCO 2019). Fixed-dose SC administration was also a viable strategy for CRS mitigation, owing to the slower rate of Mosun absorption compared with IV (Matasar et al. ASH 2020). A combination of both strategies could further improve the CRS profile. We present safety and efficacy data from the initial cohorts investigating SC Mosun administration with C1 step-up dosing in the Phase I/II study.
Methods: All pts had R/R B-NHL with ≥1 prior line of systemic therapy and ECOG PS ≤1. SC Mosun was given in 21-day cycles using two step-up dosing schedules (C1 day [D]1/C1D8/C1D15 and D1 of subsequent cycles: 5/15/45mg or 5/45/45mg). Mosun was discontinued after C8 in pts who achieved a CR, while pts with a partial response or stable disease continued Mosun for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurred. Primary objectives included evaluation of safety, tolerability, and pharmacokinetics (PK). Responses were evaluated by investigator-assessment of PET/CT scans using Cheson 2007 criteria. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019).
Results: As of June 21, 2021, 74 pts had been enrolled (5/15/45mg: 38 pts; 5/45/45mg: 36 pts). Median age was 67.0 years (range: 41-88). The most common NHL subtypes were DLBCL (31 pts), FL (21), transformed (tr) FL (10), and MCL (3). 70.0% of pts had Ann Arbor stage III or IV disease. Median number of prior lines of therapy was 3 (range: 1-9). 79.5% of pts were refractory to prior anti-CD20 therapy and 82.4% were refractory to their last prior therapy.
Median follow-up for safety was 2.5 months (range: 0.2-7.2). No dose-limiting toxicities were observed during dose-escalation. Common all-Grade (Gr) adverse events (AEs; ≥10% of pts) were injection site reaction (52.7%; Gr 1: 47.3%; Gr 2: 5.4%), CRS (24.3%), fatigue (21.6%), headache (17.6%), rash (13.5%), and pyrexia (10.8%). CRS mostly occurred in C1 and was low Gr in all pts (Gr 1: 17.6%; Gr 2: 6.8%); no Gr ≥3 CRS occurred. Gr 2 CRS occurred with a similar frequency in the 5/15/45mg and 5/45/45mg cohorts (7.9% vs 5.6% of pts, respectively). In the 5/15/45mg cohort, the 3 Gr 2 CRS events occurred after each of the C1 doses, while in the 5/45/45mg cohort, the 2 Gr 2 CRS events occurred after the first 45mg dose. Median duration of CRS was 2 days (range: 1-6) and all events resolved without sequelae. Neutropenia occurred in 12.2% of pts (Gr 2: 2.7%; Gr 3: 6.8%; Gr 4: 2.7%). Febrile neutropenia occurred in only 1 pt (Gr 3). Serious infections occurred in 3 pts (2 pneumonia, both resolved; 1 COVID-19, fatal outcome). No Mosun-related Gr 5 (fatal) AEs or Mosun-related AEs leading to Mosun discontinuation occurred.
The PK profile of SC Mosun was consistent with that previously reported, with high bioavailability (&gt;85%), a slow absorption rate, and a blunted C max. IL-6 and IFN-y kinetics in plasma were similar in both SC cohorts, with modest and delayed increases observed after the initial dose, contrasting with the more marked and rapid increases observed with IV dosing, and consistent with the low frequency and severity of CRS observed.
At data cut-off, 38 pts were efficacy evaluable. Responses were observed in 19 pts across all histologies, including 8/10 (80%) pts with R/R FL and 6/17 (35.3%) pts with R/R DLBCL/trFL.
Conclusions: SC Mosun administration with C1 step-up dosing has a favorable safety profile in pts with late-line and highly refractory B-NHL, enabling an outpatient treatment schedule without mandatory hospitalizations. Encouragingly, the 5/45/45mg schedule had a low rate of CRS that was similar to the 5/15/45mg schedule, allowing the target dose to be reached earlier. Early response data suggest that the efficacy of Mosun is not compromised by SC dosing. Compared with IV, SC Mosun is likely to improve convenience for pts and efficiency for healthcare providers. Updated efficacy data with longer follow up and depth of response will be presented.

Disclosures
Bartlett: Affimed: Research Funding; Autolus: 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; Genentech, Inc./F. Hoffmann-La Roche Ltd: 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; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment. Giri: Royal Adelaide Hospital: Current Employment. Budde: Genentech, Inc.: Consultancy; Merck, Inc: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; Mustang Bio: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Beigene: Consultancy. Schuster: Celgene: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Acerta Pharma/AstraZeneca: Consultancy; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmaclyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Merck: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; DTRM: Research Funding. Assouline: Johnson&Johnson: Current equity holder in publicly-traded company; Gilead: Speakers Bureau; Amgen: Current equity holder in publicly-traded company, Research Funding; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Jewish General Hospital, Montreal, Quebec: Current Employment; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Matasar: Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding. Canales: Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Fay: St Vincent's Hosptial, Sydney, Australia: Current Employment. Cheah: BMS: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Marlton: BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; AstraZeneca: 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; 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; Queensland Health: Current Employment; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiebking: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yin: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. To: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Li: Genentech, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Huang: F. Hoffmann-La Roche Ltd: Current Employment. Zhou: Fibrogen China: Ended employment in the past 24 months; Roche Pharma Product Development: Current Employment. Penuel: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Hear: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Sehn: Novartis: Consultancy; Debiopharm: Consultancy; Genmab: Consultancy.

OffLabel Disclosure:
Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.