Mosunetuzumab Monotherapy Continues to Demonstrate Promising Efficacy and Durable Complete Responses in Elderly/Unfit Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Elderly/unfit patients (pts) with diffuse large B-cell lymphoma (DLBCL) who are unable to tolerate standard first-line (1L) chemoimmunotherapy (CIT) due to age or pre-existing comorbidities, often receive no treatment, reduced-dose R-CHOP, or therapies such as R-CVP or R-bendamustine. Less toxic, efficacious alternatives to full-dose CIT are needed. Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. Mosun monotherapy has shown durable complete responses in pts with relapsed/refractory DLBCL in an ongoing Phase I study (Budde et al. JCO 2022). Early data from a Phase I/II, multicenter study (NCT03677154) in elderly/unfit pts with previously untreated DLBCL, showed promising efficacy with durable responses and manageable safety with 1L Mosun monotherapy (Olszewski et al. EHA 2021). Here, we report updated efficacy and safety outcomes with at least 1 year of follow-up after the end of treatment (EOT).

Methods: Eligible pts were aged ≥80 years, or 60–79 years with ≥1 activity of daily living (ADL) or instrumental ADL impaired, or reduced cardiac, renal, or liver function precluding the use of full-dose CIT. Pre-phase prednisone with or without vincristine was allowed. Pts received Cycle (C) 1 step-up dosing with IV Mosun on Days (D) 1 (1mg), 8 (2mg) and 15 (13.5 or 30mg) and 13.5mg or 30mg Mosun on D1 of each subsequent 21-day cycle (1/2/13.5mg and 1/2/30mg). Pts with a complete response (CR) stopped Mosun after 8 cycles; pts with a partial response (PR) or stable disease (SD) could continue Mosun up to 17 cycles. Primary endpoints included objective response and CR rates (assessed by PET-CT). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Tumor biomarkers were assessed by immunohistochemistry. Pts enrolled in two safety-evaluation cohorts received Mosun 1/2/13.5mg or 1/2/30mg, and pts in the expansion phase received Mosun 1/2/30mg (enrollment completed July 2021). Here, we report combined data for the two doses.

Results: As of June 01, 2022, 54 pts had received Mosun (13.5mg, n=8; 30mg, n=46) and all were efficacy evaluable. Median age was 83 years (range: 65–100), 33 (61%) pts were female, 35 (65%) had an ECOG PS 0–1, 30 (56%) had Ann Arbor Stage III–IV, and 44 (81%) had an International Prognostic Index score ≥2. Median number of cycles received was eight (range: 1–16); three pts in PR continued treatment after C8. Median follow-up was 23.3 months (range: 0‒36). Best overall response rates (ORR) and CR rates were 56% (30/54) and 43% (23/54), respectively. Responses following EOT (primary response assessment timepoint) in both dosing cohorts combined were: ORR, 43% (23/54); CR, 35% (19/54); PR, 7% (4/54); SD, 2% (1/54); progressive disease, 33% (18/54). Median duration of CR was 15.8 months (95% CI: 8.5–not estimable); of 23 pts who achieved a CR (at any timepoint), CR was maintained in 11 pts for >12 months (Figure). The 12-month progression-free survival rate was 39% (95% CI: 25.8–52.8). No new safety signals were observed; 98% of pts had ≥1 adverse event (AE); 48% had a grade (gr) 3/4 AE. An AE leading to treatment discontinuation was reported in one patient (renal failure; not related to Mosun). Fatal AEs occurred in three pts; one death from natural causes and two due to COVID-19 pneumonia (none considered Mosun-related). Common (>10%) treatment-emergent AEs were rash (31%), CRS (26%), and fatigue (26%). Ten pts had gr 1 CRS and four had gr 2. No gr 3+ CRS and no new CRS were reported since the previous cut-off. Neutropenia was reported in 15% of pts (gr 2, 2%; gr 3/4, 13%), and gr 3 febrile neutropenia was reported in one patient. Median duration of neutropenia was 12 days (range: 7‒28). Serious infections were reported in 22% of pts (gr 3, 17%; gr 5, 4% [all due to COVID-19 pneumonia]). No ICANS related to Mosun were reported. Exploratory biomarker analyses of tumor composition revealed increased levels of CD8+ T cells at baseline in responders vs non-responders.

Conclusions: Mosun monotherapy continued to demonstrate promising efficacy with durable responses and a manageable safety profile. These data support a potential future role for Mosun in elderly/unfit pts with previously untreated DLBCL and may help to identify pts whose tumors respond to treatment with bispecific antibody monotherapy.