Mosunetuzumab with Polatuzumab Vedotin Is Effective and Has a Manageable Safety Profile in Patients Aged

Abstract

Background: Treatment decision-making for elderly DLBCL patients (pts) is challenging. Advancing age is associated with an increase in the incidence of comorbidity and vulnerability to treatment-related toxicities (Thieblemont & Coiffier. J Clin Oncol 2007). Mosunetuzumab (M) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. The Phase Ib/II GO40516 study (NCT03671018) is evaluating M in combination with the anti-CD79b antibody-drug conjugate polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). In the ongoing Phase II part of the study, M-Pola showed an acceptable safety profile with promising activity in pts with R/R B-NHL (Budde et al. ASH 2021). Here, we present a subgroup analysis of the efficacy and safety of M-Pola in pts aged <65 and ≥65 years with R/R aggressive B-NHL from the Phase Ib dose-escalation and Phase II dose-expansion cohorts. Methods: All pts in this analysis had DLBCL (including transformed follicular lymphoma and follicular lymphoma grade [Gr] IIIB), an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and ≥1 prior line of therapy, including an anti-CD20 Ab. Treatment cycles were 21 days. Pola (1.8mg/kg intravenous [IV] infusion) was given on Day (D)1 of Cycle (C)1-6. M (IV infusion) was given with step-up dosing during C1 to mitigate cytokine release syndrome (CRS), and the recommended Phase II dose was used in the Phase II dose-expansion cohort (1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3-8). Pts with stable disease or a partial response at the end of C8 could continue M for a total of 17 cycles, while pts with a complete response (CR) discontinued M after C8. In the Phase II expansion cohort, mandatory hospitalization was not required for M administration. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of March 15, 2021, with a median follow-up of 5.3 months (range: 0.7-23.7 months), 60 pts with R/R DLBCL had received M-Pola: 24 (40%) were aged <65 years and 36 (60%) were aged ≥65 years. At study entry, for pts aged ≥65 years, the median age was 73 years (range: 65-83), 53% had ECOG PS 1 and 8% had PS 2, 50% had International Prognostic Index 3-5, 81% had Ann Arbor stage III/IV disease, and 81% and 72% were refractory to a prior anti-CD20 Ab and to last prior therapy, respectively. There were more pts <65 years than pts ≥65 years with high lactate dehydrogenase (LDH; 63% vs 44%, respectively), with ≥3 prior lines of therapy (67% vs 56%), and refractory to CAR T-cell therapy (38% vs 25%; Table). Compared with younger pts, those aged ≥65 years had a numerically higher ORR (72% [95% CI: 55-86] vs 54% [95% CI: 33-75]) and CR rate (56% [95% CI: 38-72] vs 38% [95% CI: 19-59]). The rate of Gr 3-4 adverse events (AEs) was lower in pts ≥65 years than in those <65 years (39% vs 58%, respectively), with fewer neutropenia events occurring (14% vs 33%); the rate of serious AEs of any Gr was similar (39% vs 33%). Five pts ≥65 years discontinued M and/or Pola due to treatment-related AEs compared with one pt <65 years. The rate of CRS was comparable in pts aged ≥65 and <65 years (17% vs 21%), all CRS events were low-Gr (≥65 vs <65 years: Gr 1, 14% vs 21%; Gr 2, 3% vs 0%), and all CRS events resolved. Rates of serious AEs of infection were comparable in pts aged ≥65 and <65 years (11% vs 17%, respectively). Rates of peripheral neuropathy were 42% in pts aged ≥65 years vs 21% in pts aged <65 years, with most events Gr1-2 (≥65 vs <65 years: 1 vs 2 Gr 3 events). After the first M-Pola dose, pharmacodynamic changes in interferon-α and T-cell activation in peripheral blood were similar across age groups. Conclusions: M-Pola is effective and has a manageable safety profile in pts with heavily pretreated DLBCL, including older pts who may have more comorbidities and fewer treatment options, such as those who are poor candidates for CAR T-cell therapy. Numerically higher ORR and CR rates were seen in pts aged ≥65 years, although longer follow-up is required. Comparable rates of CRS and serious AEs were observed across age groups. Enrollment in the Phase II study with no mandatory hospitalization is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal