Single-Agent Mosunetuzumab Is a Promising Safe and Efficacious Chemotherapy-Free Regimen for Elderly/Unfit Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Introduction: Up to 30% of patients (pts) aged ≥75 years do not receive standard chemoimmunotherapy (CIT) as first-line (1L) treatment for diffuse large B-cell lymphoma (DLBCL) due to concerns about frailty and comorbidities. Poor outcomes are commonly reported for elderly/unfit pts with 1L DLBCL who receive no treatment, reduced-dose R-CHOP or other therapies such as R-CVP and R-bendamustine (Morrison, et al. J Geriatr Oncol 2020); less toxic, efficacious alternatives to full-dose CIT are needed. Mosunetuzumab (Mosun) is a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Single-agent Mosun has shown promising efficacy (including durable complete responses [CRs]) and tolerable safety in relapsed/refractory DLBCL pts in an ongoing Phase I study (GO29781; NCT02500407; Bartlett, et al. ASCO 2019, Schuster, et al. ASH 2019). Here we present early clinical data with Mosun as 1L therapy for elderly/unfit pts with DLBCL.

Methods: GO40554 (NCT03677154) is a Phase I/II, open-label, multicenter study. We report data from Cohort B, designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of Mosun in pts with 1L DLBCL who are unable to tolerate full-dose CIT. Two safety evaluation cohorts were planned to receive Mosun at 13.5mg and 30mg, followed by an expansion phase. No safety concerns emerged following evaluation of the two safety cohorts. Eligible pts were aged ≥80 years or 60-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL, or with impairment in cardiac, renal or liver function precluding the use of full-dose CIT. After optional pre-phase treatment with prednisone with or without vincristine, pts received Mosun intravenously with step-up dosing on Day (D) 1, 8 and 15 of Cycle (C) 1, followed by a fixed dose on D1 of each subsequent 21-day cycle. Interim response assessment (IRA) occurred after C4 and primary response assessment (PRA) occurred after C8, with an option to continue up to maximum 17 cycles in case of partial remission (PR) following PRA.

Results: As of May 27, 2020, 19 pts in Cohort B had received Mosun (1mg [C1 D1]/2mg [C1 D8]/13.5mg [C1 D15 onwards], n=8; 1/2/30mg, n=11). Eight pts were enrolled in the 13.5mg safety evaluation cohort and 11 enrolled in the 30mg safety cohort and expansion (7+4 respectively). Median age was 84 (range: 67-100) years, 14 (74%) pts were women, 10 (53%) had Ann Arbor stage III-IV and 17 (90%) had an IPI score ≥2. Median Mosun cycles received was 6 (range: 2-9; one pt in PR continued treatment). Among 19 pts, 16 (84%) had ≥1 adverse event (AE), 13 (68%) had ≥1 AE related to Mosun and 7 (37%) experienced a Grade (Gr) 3-4 AE, of which 4 were related to Mosun. No fatal AEs were observed. The most common (>10%) treatment-emergent AEs were cytokine release syndrome (CRS; n=9, 47%), rash (n=4, 21%), neutropenia, nausea, decreased appetite, dry mouth, fatigue, pain and muscle spasms (all n=2, 11%). All CRS events were Gr 1 by ASTCT consensus criteria (Lee, et al. Biol Blood Marrow Transplant 2019); no pts experienced hypotension, hypoxia or required tocilizumab or steroid treatment. No severe (Gr ≥3) neurologic AEs were observed. Gr 2 (ICAN) neurotoxicity was observed in one (5%) pt on C1D2 with symptoms of inability to answer questions, drowsiness, weakness and somnolence, combined with Gr 1 CRS (fever and tachycardia). The event resolved after 2 days and was considered related to Mosun. Eight (42%) pts discontinued Mosun early due to progressive disease (PD) between C2-C6. No pts discontinued Mosun due to an AE. Among all treated pts, the overall response rate was 58% (11/19) and CR rate was 42% (8/19). At Mosun dose 13.5mg, 3/8 pts (38%) achieved a CR, 2 (25%) had a PR and 3 (38%) had PD at the PRA. At Mosun dose 30mg, response was available at IRA: 5/11 pts (45.5%) achieved a CR, 1 (9%) had a PR and 5 (45.5%) had PD. Of the 8 pts with PD (from both dosing cohorts), 5 have received salvage therapy post progression. Figure 1 shows a durable response of almost a year for the first responder. Correlative studies of T-cell response by flow cytometry and cytokine expression, and PK analyses are ongoing and will be provided.

Conclusions: Early clinical data indicate that single-agent Mosun confers notable efficacy and remarkable tolerability for previously untreated elderly/unfit DLBCL pts. Mosun is a promising chemotherapy-free regimen for patients who otherwise have limited options.

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