Subcutaneous Mosunetuzumab Leads to High Rates of Durable Responses, Low Rates of Cytokine Release Syndrome, and Non-Inferior Exposure Compared with Intravenous Administration in Patients with Relapsed/Refractory Follicular Lymphoma: Primary Analysis of a Pivotal Phase II

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody approved by the FDA and EMA for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy by intravenous (IV) administration. In a Phase II study (NCT02500407), fixed-duration Mosun IV had a manageable safety profile and induced a high rate of complete responses (CRs; 60%) in patients (pts) with R/R FL (Budde et al. Lancet Oncol 2022). A subcutaneous (SC) formulation of Mosun, aimed at further improving safety and pt convenience, is currently under evaluation. Here we present data from the primary analysis of Mosun SC in pts with R/R FL.

Methods: Eligible pts had R/R FL Grade (Gr) 1-3a and ≥2 prior therapies. Mosun was administered by a single SC injection (≤1mL over 30s-2min) in 21-day cycles with step-up dosing in Cycle (C)1 (C1 Day [D]1, 5mg; C1D8, 45mg; C1D15, 45mg; C2D1 and onwards, 45mg). Corticosteroid prophylaxis was required during C1; hospitalization was not mandatory. Pts with a CR by C8 completed treatment; those with a partial response or stable disease continued therapy for up to 17 cycles. The primary objective was pharmacokinetic non-inferiority (PKNI) of Mosun SC to Mosun IV (historical control); co-primary pharmacokinetic (PK) endpoints were serum C_trough(C3) and model-predicted cumulative serum AUC_D0-84. Non-inferiority was defined as lower bounds of the 90% confidence interval (CI) of geometric mean ratios (GMRs) being above the pre-defined margin of 0.8. Secondary endpoints included overall response rate (ORR), CR rate, duration of response (DOR) and of CR (DOCR), progression-free survival (PFS), and overall survival (OS).

Results: Between Apr 2021 and Feb 2023, 94 pts were enrolled.At data cut-off (Feb 1, 2024), median time on study was 20.7 months (range: 1-34). Median age was 65 years (range: 35-84), 87% had Ann Arbor stage III/IV disease, and 56% had FLIPI score ≥3 at study entry. Median number of prior therapy lines was 3 (range: 2-9); 44% had progressive disease (PD) within 24 months from start of first-line therapy; 63% and 67% were refractory to their last therapy and any prior anti-CD20 therapy, respectively; 46% were double refractory to any prior anti-CD20 therapy and alkylating agent. Median number of cycles received was 8 (range: 1-17).

The PKNI analysis included 68/94 SC (only pts treated with updated drug formulation) and 90/90 IV PK-evaluable pts. The co-primary PK endpoints were met, with 90% CI lower bounds of the GMRs above 0.8 for both C_trough(C3) (GMR 1.39 [90% CI: 1.2-1.6]) and AUC_D0-84 (GMR 1.06 [90% CI: 0.9-1.2]).

In the Mosun SC group (n=94), ORR and CR rate (IRC-assessed) were 74% and 59%, respectively. Estimated 18-month DOR and DOCR were 60% (95% CI: 45.8-73.3) and 66% (95% CI: 51.0-80.2), respectively. Median PFS was 18.5 months (95% CI: 12.9-24.0); median OS was not reached.

Most common all-grade adverse events (AEs) were injection-site reactions (ISRs; 61%), fatigue (35%), and cytokine release syndrome (CRS; 30%). ISRs were all Gr 1/2 and non-serious; none led to treatment discontinuation. CRS events (Gr 1/2 28%; Gr 3 2%) were manageable; serious CRS events occurred in 15% of pts. All CRS events occurred in C1, mostly on C1D1 and C1D8; all resolved. Median time to CRS onset was 2.5 days; median duration was 2 days. Of 28 pts with CRS, 8 received tocilizumab and 6 received steroids. Suspected immune effector cell-associated neurotoxicity syndrome occurred in 3 pts (lethargy, n=2; memory impairment, n=1), with 2 events concurrent with CRS. All events were Gr 1, occurred during C1, and resolved without steroid use. Gr 3/4 and serious AEs were reported in 49% and 39% of pts, respectively. Mosun-related AEs led to treatment discontinuation in 3 pts. Gr 5 AEs (excluding PD) were reported in 5 pts (COVID-19 pneumonia, n=2; COVID-19, n=1; hemophagocytic lymphohistiocytosis, n=1 [with active Epstein-Barr virus, cytomegalovirus, and lymphoma transformation]; general physical health deterioration, n=1).

Conclusions: The study's co-primary PK endpoints were met, demonstrating non-inferior PK for Mosun SC vs Mosun IV. Fixed-duration Mosun SC achieved high rates of deep and durable responses in pts with R/R FL and ≥2 prior lines of therapy. The safety profile was manageable, with low CRS incidence and severity. Mosun SC potentially enhances pt convenience and practice efficiency, and can be delivered in an outpatient setting.

Bartlett:ADC Therapeutics: Research Funding; Washington University School of Medicine: Current Employment; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Autolus: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees. Sehn:AbbVie; Amgen; AstraZeneca; Beigene; BMS/Celgene; Genmab; Kite/Gilead; Incyte; Janssen; Merck; Seagen; F. Hoffmann-La Roche Ltd; Genentech, Inc.: Consultancy; AbbVie; Amgen; AstraZeneca; Beigene; BMS/Celgene; Genmab; Kite/Gilead; Incyte; Janssen; Merck; Seagen; F. Hoffmann-La Roche Ltd; Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd; Genentech, Inc.; Teva: Research Funding. Assouline:Novartis Canada Inc.: Research Funding; Genentech/Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; F. Hoffman-La Roche Ltd.: Consultancy, Honoraria; Ipsen: Consultancy; Pfizer: Consultancy. Giri:Royal Adelaide Hospital: Current Employment. Kuruvilla:F. Hoffmann-La Roche Ltd, AstraZeneca, Merck, Novartis: Research Funding; DSMB Karyopharm: Other; AbbVie, Amgen, AstraZeneca, BMS, Genmab, Gilead, Incyte, Janssen, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Seattle Genetics: Honoraria; AbbVie, BMS, Gilead, Merck, F. Hoffmann-La Roche Ltd, Seattle Genetics: Consultancy. Schuster:AbbVie, AstraZeneca, BeiGene, BioNTech, Caribou Biosciences, Celgene/Juno Therapeutics, Genentech/Roche, Genmab, Janssen, Kite Pharmaceuticals, Legend Biotech, Novartis, viTToria biotherapeutics: Consultancy; Celgene/Juno Therapeutics, Genentech/Roche, Merck, Novartis: Research Funding; AstraZeneca, BeiGene, Celgene/Juno Therapeutics, Genentech/Roche, Janssen, Legend Biotech, Nordic Nanovector, Novartis: Honoraria; Caribou Biosciences, Nordic Nanovector, Novartis: Membership on an entity's Board of Directors or advisory committees. Yoon:Janssen, Novartis, F. Hoffmann-La Roche Ltd, Genentech, Inc.: Consultancy; Janssen: Honoraria; F. Hoffmann-La Roche Ltd, Genentech, Inc.: Research Funding. Fay:St Vincent's Hospital: Current Employment. Hess:AstraZeneca: Consultancy, Honoraria, Other: Travel Support; AbbVie, ADC, AstraZeneca, BMS, Incyte, Janssen, Lilly, Miltenyie, Novartis, PiereFabre, F. Hoffmann-La Roche Ltd, Sobi: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Other: Travel support; BMS: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Lilly: Consultancy, Honoraria, Other: Travel support, Research Funding; Miltenyie: Consultancy, Honoraria, Other: Travel support; Abbvie: Consultancy, Honoraria, Other: Travel support, Research Funding; MSD: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support; Incyte, AbbVie, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd: Research Funding. Dreyling:AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding; AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees. Gutierrez:University Hospital of Salamanca: Current Employment; Amgen, Sanofi: Honoraria. Cybulski:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Kwan:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Penuel:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tracy:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Kuruvilla:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Chen:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd., Pfizer, Poseida, Editas, CVS: Current equity holder in publicly-traded company. Wiebking:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Wei:Genentech, Inc.: Current Employment, Patents & Royalties; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Budde:AstraZeneca, Mustang Therapeutics, Merck: Research Funding; ADC Therapeutics, AstraZeneca, AbbiVe, Roche, Genentech, Genmab, Jenssen, Regeneron: Consultancy; AstraZeneca, Mustang Therapeutics, Merck: Research Funding; ADC Therapeutics, AstraZeneca, AbbVie, F. Hoffmann-La Roche Ltd, Genentech, Inc., Genmab, Jenssen, Regeneron: Consultancy; City of Hope National Medical Center: Current Employment.

All study therapy constituted investigational or off-label use. Mosunetuzumab is a bispecific CD20-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.