Subcutaneous Mosunetuzumab in Relapsed or Refractory B-Cell Lymphoma: Promising Safety and Encouraging Efficacy in Dose Escalation Cohorts
Authors: Matasar Matthew J , Cheah Chan Yoon , Yoon Dok Hyun , Assouline Sarit E , Bartlett Nancy L. , Ku Matthew , Giri Pratyush , Johnston Anna , Flinn Ian W. , Goy Andre H. , Tzachanis Dimitrios , O'Hear Carol , Yin Shen , To Iris , Sarouei Kati , Li Chi-Chung , Bender Brendan C. , Penuel Elicia M. , Huang Huang , Budde L. Elizabeth 
Published: November 2020

Introduction: More effective, less toxic treatments with convenient administration are needed for patients (pts) with relapsed/refractory (R/R) B-cell lymphoma (B-NHL). Mosunetuzumab (Mosun) is a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. In an ongoing Phase I/Ib study (GO29781; NCT02500407), Mosun has shown promising efficacy and tolerable safety in pts with R/R B-NHL when administered intravenously (IV) in step-up doses (Bartlett, et al. ASCO 2019, Schuster, et al. ASH 2019). Subcutaneous (SC) administration of Mosun is an alternative approach to minimize the risk of cytokine release syndrome (CRS), a key adverse event (AE) associated with T-cell engaging immunotherapies. Other potential benefits of SC dosing include reduced healthcare resource utilization and increased convenience. This is the first report of clinical data with Mosun SC in pts with R/R B-NHL.
Methods: GO29781 is a Phase I/Ib, open-label, multicenter dose-escalation and expansion study of Mosun in R/R B-NHL. Pts included in this report received single-agent Mosun SC on Day 1 of each 21-day Cycle (Q3W), for 8 cycles in pts with complete response (CR) and up to 17 cycles in pts with partial response or stable disease. Dose escalation used a standard 3+3 design; doses from 1.6-20 mg were assessed. Key outcome measures included best objective response (per Cheson 2007 criteria), tolerability and maximum tolerated dose (MTD).
Results: As of January 21 2020, 23 pts had received Mosun SC (diffuse large B-cell lymphoma, n=10; follicular lymphoma [FL], n=5; marginal-zone lymphoma [MZL], n=3; primary mediastinal large B-cell lymphoma, n=2; transformed [tr] FL, n=1; trMZL, n=1; tr nodular lymphocyte-predominant Hodgkin lymphoma, n=1). Median prior systemic therapies was 4 (range: 1-8); five pts (22%) had received prior chimeric antigen receptor T-cell therapy. Thirteen pts (57%) were refractory to last prior therapy and 16 (70%) were refractory to prior anti-CD20 therapy.
The MTD was not reached. One dose-limiting toxicity (Grade [Gr] 4 neutropenia; resolved) was observed at dose 1.6mg. Among the 23 safety-evaluable pts, 22 (96%) experienced ≥1 AE; no AEs led to treatment discontinuation. Common (&gt;20%) AEs related to Mosun SC were CRS (n=8, 35%), headache (n=5, 22%; all Gr 1) and injection site reaction (n=5, 22%; all Gr 1). All CRS events, graded by Lee criteria (Lee, et al. Blood 2014), occurred during Cycle 1 and were Gr 1 (n=6, 26%) or Gr 2 (n=2, 9%). In contrast to the Q3W fixed-dosing IV cohort, where 15% of pts experienced Gr 2 CRS at doses 0.05-2.8mg, no Gr 2 CRS occurred in the SC cohort at doses &lt;13.5mg. In SC pts, CRS events resolved without tocilizumab treatment, intensive care unit admission or use of vasopressors. One pt required low-flow oxygen. No neurological symptoms (defined as any Preferred Terms in the nervous system disorders and psychiatric disorders system organ class) associated with CRS were reported. Neurological symptoms not associated with CRS occurred in nine pts (39%; all Gr 1) with headache (n=5, 22%) and tinnitus (n=2, 9%) as the most common AEs.
Among the 22 efficacy-evaluable pts across all dose levels, overall response rates and CR rates were 86% (6/7) and 29% (2/7) in indolent NHL pts and 60% (9/15) and 20% (3/15) in aggressive NHL pts, respectively. After a median 6.9 months (range: 1.3-22.1) on study for all SC pts, all but one CR pt remained in remission at the cut-off date.
The pharmacokinetic (PK) profile of Mosun SC is characterized by a slow absorption rate (observed Tmax at 72 hours post-dose and Cmax reduced by ~70% versus IV) and high bioavailability (&gt;75%), supporting the use of SC dosing for CRS mitigation. Consistent with reduced CRS, lower peak IL-6 levels were observed with SC dosing, with delayed onset versus Mosun IV.
Conclusions: Mosun SC demonstrated a manageable safety profile, encouraging efficacy and a favorable PK profile in heavily pretreated R/R B-NHL pts. CRS events seen in Cycle 1 were mild, transient and required minimal intervention and no Gr ≥3 CRS events were reported. Notably, less frequent Gr 2 CRS events were observed with Mosun SC at 7-fold higher dose levels versus the IV fixed-dosing group. These results support continued dose escalation and optimization of Mosun SC in R/R B-NHL. Updated clinical, PK and biomarker data, including approximately 20 additional pts from an interim expansion cohort, will be presented.

Disclosures
Matasar: Genentech, Inc.: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Assouline:Takeda: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding. Bartlett:ADC Therapeutics: Consultancy; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; Autolus: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Ku:F. Hoffmann-La Roche: Honoraria. Giri:Royal Adelaide Hospital: Current Employment. Johnston:MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees. Flinn:Loxo: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; BeiGene: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Nurix Therapeutics: Consultancy; Acerta Pharma: Research Funding; Calithera Biosciences: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; IGM Biosciences: Research Funding; Agios: Research Funding; Curio Science: Consultancy; Infinity Pharmaceuticals: Research Funding; Trillium Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; ArQule: Research Funding; Takeda: Consultancy, Research Funding; Merck: Research Funding; Curis: Research Funding; AbbVie: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Kite Pharma: Consultancy, Research Funding; Forty Seven: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; F. Hoffmann-La Roche: Research Funding. Goy:Celgene: Honoraria, Research Funding; Constellation: Research Funding; AbbVie: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; RCCA/OMI: Current Employment; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; MD Anderson: Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; Infinity: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Morphosys: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role. Tzachanis:Fate: Research Funding; Incyte: Research Funding; Genetech: Research Funding; BMS: Research Funding; Takeda: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy; Jazz: Consultancy; Magenta: Consultancy; Kyowa Kirin: Consultancy; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Yin:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. To:Genentech, Inc.: Current Employment. Sarouei:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Li:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bender:Genentech, Inc.: Current Employment, Current equity holder in private company. Penuel:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Huang:F. Hoffmann-La Roche: Current Employment. Budde:AstraZeneca: Speakers Bureau; Merck, Amgen, AstraZeneca, Mustang Therapeutics: Research Funding; F. Hoffmann-La Roche, Kite Pharma: Consultancy.

OffLabel Disclosure:
Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.