Subcutaneous Mosunetuzumab Is Active with a Manageable Safety Profile in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphomas (B-NHLs): Updated Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Bi-mAb) that redirects T cells to eliminate malignant B cells, is the first Bi-mAb approved for R/R follicular lymphoma (FL; EMA 2022; Budde et al. Lancet Oncol 2022) and can be administered intravenously in the outpatient setting with a fixed treatment duration. A subcutaneous (SC) formulation that aims to improve safety and convenience is under evaluation. We present results for SC Mosun in a larger population with longer follow-up than previously reported (Bartlett et al. ASH 2021).

Methods: GO29781 is a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with R/R B-NHL (NCT02500407). Pts with ≥1 prior line of systemic therapy (dose-escalation) or ≥2 prior lines (dose-expansion) were included. SC Mosun was administered with step-up dosing in Cycle (C) 1, then given on Day (D) 1 of subsequent 21-day cycles. The first 2 dose-escalation groups received Mosun 5mg on C1D1, 15mg or 45mg on C1D8, and 45mg on C1D15 and D1 from C2 onwards (5/15/45mg [Group 1] and 5/45/45mg [Group 2], respectively). A third group received Mosun 5mg on C1D1, 45mg on C1D8, 90mg on C1D15 and C2D1, and 45mg on D1 from C3 onwards (5/45/90/90/45mg [Group 3]). Pts with a complete response (CR) after 8 cycles completed therapy; pts with a partial response or stable disease continued treatment up to 17 cycles. Primary objectives included safety, tolerability and identification of the recommended Phase II dose.

Results: At data cut-off (May 20, 2022) 89 pts with R/R B-NHL received SC Mosun (Group 1: n=39, Group 2: n=47, Group 3: n=3). Most common histologies were diffuse large B-cell lymphoma (56%), transformed FL (19%) and FL (12%). Median (range) age was 68 years (24–88). Median number of prior systemic therapies was 3; 85.1% and 83.9% of pts were refractory to their last prior therapy or prior anti-CD20 therapy, respectively; 32.6% had received prior CAR T-cell therapy. Median (range) time on study was 9.9 months (m; 0.4–19.7) and cycles completed was 5 (1–17). No dose-limiting toxicities were observed in dose escalation. Most common all-Grade (Gr) adverse events (AEs) were injection-site reaction (62%; all Gr 1/2) and cytokine release syndrome (CRS; 27%; all Gr 1/2). Gr 3/4 and serious AEs were reported in 49% and 45% of pts, respectively. One AE led to Mosun discontinuation (COVID-19; Group 1). Gr 5 AEs were reported in 5 pts; none were considered Mosun-related by investigators (Group 1: n=3 [COVID-19 n=2; large intestine perforation n=1]; Group 2: n=2 [COVID-19 pneumonia and septic shock]). CRS was reported in 15/39 pts (38%), 8/47 pts (17%) and 1/3 pts in Groups 1, 2 and 3, respectively. Most CRS events occurred during C1. Median onset time since prior Mosun and median duration was 2 days (ranges 0–4 and 1–6, respectively). CRS events were low Gr (Gr 1: 18%; Gr 2: 9%; Figures 1 and 2) and all resolved; 2 pts (2%) received corticosteroids and 4 (5%) received tocilizumab for CRS. Neutropenia was reported in 19 pts (21%; Gr 3/4 in 17 [19%]) and febrile neutropenia in 1 pt (1%; Gr 3); median (range) neutropenia duration was 8 days (2–64). Serious infections were reported in 12 (14%) pts (Gr 3/4: n=8; Gr 5: n=4). Treatment-related neurological AEs possibly consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 3 pts (3%; all Gr 1: lethargy, memory impairment, and ICANS [confusion] with Gr 1 CRS); all resolved. Tumor flare was reported in 4 pts (4%; Gr 2: n=2; Gr 3: n=2); all resolved. All pts with indolent NHL (iNHL; all FL; 11/11) and 75/76 pts with aggressive NHL (aNHL) were enrolled ≥3 m prior to cut-off and included in the efficacy analysis. Overall response rate was 82% in iNHL and 36% in aNHL; CR rate was 64% in iNHL and 20% in aNHL, with 18/22 CRs (82%) ongoing at data cut-off. Median duration of response was 6.7 m (95% CI: 4.8–not estimable) in aNHL and not reached in iNHL (9-m event-free rate: 78% [95% CI: 51–100]).

Conclusions: SC Mosun demonstrated single-agent activity similar to the intravenous formulation in pts with R/R B-NHL. SC Mosun with C1 step-up dosing had a manageable safety profile, including low CRS rates across dose schedules. Based on exposure-response considerations regarding tolerability and clinical activity, 5/45/45mg was chosen as the recommended dose. SC Mosun could improve outcomes in R/R B-NHL while increasing convenience and reducing healthcare resource utilization.