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
Elizabeth L. Budde, Nancy L. Bartlett, Pratyush Giri, Stephen J. Schuster, Sarit Assouline, Sung‐Soo Yoon, Keith Fay, Matthew J. Matasar, Norma C. Gutiérrez, Paula Marlton, Martin Dreyling, Dok Hyun Yoon, Georg Heß, John Radford, Volker Wiebking, Shen Yin, Eva Cybulski, David C. Turner, Huang Huang, Mingzhu Zhou, Elicia Penuel, Michael C. Wei, Laurie H. Sehn
Abstract
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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal