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399 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: New Agents
Hematology Disease Topics & Pathways:
Biological, Diseases, Therapies, Non-Hodgkin Lymphoma, immunotherapy, Lymphoid Malignancies
Sunday, December 2, 2018: 12:30 PM
Pacific Ballroom 20 (Marriott Marquis San Diego Marina)

Lihua E Budde1, Laurie H Sehn, MD, MPH2, Sarit Assouline, MD3, Ian W. Flinn, MD, PhD4, Iris Isufi, MD5, Sung-Soo Yoon, MD, PhD6, Won-Seog Kim7*, Matthew J Matasar, MD, MS8, Loretta J. Nastoupil, MD9, Raoul Santiago10*, Youngil Koh, MD, PhD6, Genevive Hernandez11*, Chi-Chung Li11*, Priya R Kulkarni11*, Bruce McCall11*, Scott McClellan11*, Shen Yin11, Vinita Gupta11*, Yu-Waye Chu11* and Nancy L. Bartlett, MD12

1City of Hope, Duarte, CA
2BC Cancer Centre for Lymphoid Cancer and University of British Columbia, Vancouver, BC, Canada
3McGill University Jewish General Hospital, Montreal, QC, Canada
4Sarah Cannon Research Institute, Nashville, TN
5Yale University, New Haven, CT
6Seoul National University Hospital, Seoul, Korea, Republic of (South)
7Samsung Medical Center, Seoul, Korea, Republic of (South)
8Memorial Sloan Kettering, New York, NY
9MD Anderson Cancer Center, Houston, TX
10Jewish General Hospital, Montreal, QC, Canada
11Genentech Inc, South San Francisco, CA
12Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO

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: Verastem: Consultancy, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Forty Seven: Research Funding; BeiGene: Research Funding; Incyte: Research Funding; ArQule: Research Funding; Calithera: Research Funding; Seattle Genetics: Research Funding; Verastem: Research Funding; Agios: Research Funding; Curis: Research Funding; Forma: Research Funding; Constellation: Research Funding; Takeda: Research Funding; Portola: Research Funding; Infinity: Research Funding; Celgene: Research Funding; Merck: Research Funding; Kite: Research Funding; Janssen: Research Funding. Isufi: Novartis: Consultancy; Genentech: 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.

*signifies non-member of ASH