Mosunetuzumab, a Full-Length Bispecific CD20/CD3 Antibody, Displays Clinical Activity in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (NHL): Interim Safety and Efficacy Results from a Phase 1 Study
Authors: Budde Lihua E , Sehn Laurie H , Assouline Sarit , Flinn Ian W. , Isufi Iris , Yoon Sung-Soo , Kim Won-Seog , Matasar Matthew J , Nastoupil Loretta J. , Santiago Raoul , Koh Youngil , Hernandez Genevive , Li Chi-Chung , Kulkarni Priya R , McCall Bruce , McClellan Scott , Yin Shen , Gupta Vinita , Chu Yu-Waye , Bartlett Nancy L. 
Published: October 2019

Abstract
Introduction: Mosunetuzumab is a full-length bispecific CD20/CD3 antibody that redirects endogenous T-cells to kill malignant B-cells by concomitantly binding to CD3 on T-cells and CD20 on B-cells. We report results of an ongoing multicenter Phase 1/1b study (NCT02500407) evaluating mosunetuzumab in relapsed/refractory (R/R) B-cell NHL patients (pts).
Methods: Pts received mosunetuzumab intravenously (IV) as follows: Group A, mosunetuzumab administered on day (D) 1 of each 21-day cycle (C); and Group B, ascending doses of mosunetuzumab administered on D1, D8, and D15 of C1, then at a fixed dose on D1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Single-pt dose escalation converting to a 3+3 design was used in Group A; standard 3+3 escalation was used in Group B. Additional pts were enrolled to further characterize clinical activity at cleared dose levels. Primary outcome measures are maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs), tolerability, pharmacokinetics (PK), and best objective response.
Results: As of 13 April 2018, 98 pts were enrolled to receive mosunetuzumab (diffuse large B-cell lymphoma [DLBCL]/transformed [tr] follicular lymphoma [FL] n=55, FL n=29, mantle cell lymphoma n=3; other NHL n=11; Table 1). The median duration of treatment was 81 days (range 8-162 days) in Group A and 68 days (range 1-306 days) in Group B. 26 pts remain on treatment and 18 completed treatment, of whom 10 remain in follow-up. 54 pts (55%) discontinued treatment due to disease progression (n=43, 44%), withdrawal of consent (n=5, 5%), adverse events (AEs) (n=2, 2%), use of another anticancer agent (n=2, 2%), physician decision (n=1, 1%) or death (n=1, 1%; hemophagocytic lymphohistiocytosis). Doses up to 2.8mg were assessed in Group A (n=33) and up to 1.0/2.0/13.5mg in Group B (the C1D1/C1D8/C1D15 dose; subsequent doses = C1D15 dose; n=65). DLTs were reported in 6 pts: neutropenia (n=2, both grade 4), cytokine release syndrome (CRS; n=1, grade 2), increased liver transaminases (grade 4) and hepatic encephalopathy (grade 3) (n=1), hypotension (n=1, grade 3) and anemia (n=1, grade 3). The MTD has not yet been reached in either group. Safety was similar in both groups even with higher dose levels tested in Group B (Table 2). The majority of treatment-emergent AEs occurred during Cycle 1. CRS was the most frequently reported drug-related AE; occurred in 21/98 (21%) pts and mostly occurred with the first dose. All cases of CRS were grade 1-2 per Lee et al. (Blood 2014) grading criteria. Grade ≥3 AEs occurred in 51/98 (52%) pts, of which 22/98 (22%) were considered treatment-related. Grade ≥3 treatment-emergent neutropenia was observed in 13/98 (13%) pts. One case of febrile neutropenia was reported (assessed as unrelated to study drug); no neutropenia-related infections were reported. Only one treatment-related grade ≥3 neurotoxicity was reported (grade 3 hepatic encephalopathy). One fatality from hemophagocytic lymphohistiocytosis in a pt with suspected chronic active Epstein-Barr virus infection was attributed to study treatment and one pt died of hepatic failure 26 days after the first dose; considered possibly related to treatment. Mosunetuzumab displayed a half-life of 6-11 days. Pharmacodynamic activity was evident from peripheral CD8+ and CD4+ T-cell activation following mosunetuzumab administration. Mosunetuzumab exhibited anti-tumor activity at doses ≥1.2mg (Figure 1). Among pts receiving doses ≥1.2mg, 66 patients (18 FL, 39 DLBCL/trFL and 9 other histologies) had at least 3-month follow-up and were considered efficacy-evaluable. Objective responses were observed in 27/66 (41%) evaluable pts, including 11/18 (61%) FL pts and 13/39 (33%) DLBCL/ trFL. 18 pts (27%) had a complete response (CR), including 50% (9/18) of FL pts and 21% (8/39) of DLBCL/trFL pts. Responses were observed in pts considered refractory to anti-CD20 therapy and in pts who had relapsed following CD19-directed CAR-T therapy. CRs appear durable, with all pts achieving a CR remaining in remission (median follow-up 372 days, range 95- 690 days).
Conclusions: Mosunetuzumab is clinically active in R/R B-cell NHL. The safety profile, with MTD not yet reached and with most AEs being low-grade and manageable, appears favorable compared to current standard anti-lymphoma therapies including T-cell directed agents. Mosunetuzumab monotherapy shows promising and durable efficacy in FL and in DLBCL.

Disclosures
Sehn: Morphosys: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Flinn:Agios: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; BeiGene: Research Funding; Trillium: Research Funding; Gilead: Research Funding; ArQule: Research Funding; Verastem: Consultancy, Research Funding; Curis: Research Funding; Forma: Research Funding; Merck: Research Funding; Kite: Research Funding; Calithera: Research Funding; Takeda: Research Funding; Constellation: Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Infinity: Research Funding. Isufi:Genentech: Consultancy; Novartis: Consultancy. Kim:Kyowa-Kirin: Research Funding; Celltrion: Honoraria, Research Funding; J&J: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Merck: Research Funding. Matasar:Seattle Genetics: Honoraria. Nastoupil:Karus: Research Funding; TG Therappeutics: Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Juno: Honoraria; Gilead: Honoraria; Genentech: Honoraria, Research Funding; Spectrum: Honoraria; Janssen: Research Funding. Hernandez:Genentech: Employment. Li:Genentech: Employment, Equity Ownership. Kulkarni:Genentech: Employment. McCall:Genentech: Employment. McClellan:Genentech: Employment. Yin:Genentech: Employment, Equity Ownership. Gupta:Genentech: Employment, Equity Ownership. Chu:Genentech: Employment, Equity Ownership. Bartlett:Millennium: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding.