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

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 (>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, ustralia 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. HuangF. 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.