Mosunetuzumab in combination with zanubrutinib is safe in patients with relapsed/refractory follicular lymphoma: Safety run-in results from the FIL-mozart Phase II study

Abstract Introduction Treatment of relapsed/refractory (R/R) follicular lymphoma (FL) is shifting toward chemo-free regimens to improve efficacy and reduce toxicity. Zanubrutinib (Z), a BTK inhibitor (BTKi), showed activity with immunotherapy in the ROSEWOOD trial (Zinzani et al, JCO 2023). We therefore decided to evaluate Z in combination with subcutaneous mosunetuzumab (sc M), a highly active bispecific CD20xCD3 antibody (Budde et al, Lancet Oncol 2022), in the FIL-MOZART phase II trial. Here, we report feasibility, safety, and preliminary efficacy from the safety run-in (SRI) phase (from C1D1 to C3D28) of this study (EU CT 2023-506049-52-00). Methods The FIL-MOZART trial is a FIL sponsored international trial, including sites in Italy and Australia. The study aims to enroll 56 adult pts with R/R CD20+ histologically confirmed classic FL who have received at least one and up to three prior lines of systemic anti-CD20-based therapy. The treatment consists of a two-week oral Z pre-phase followed by a 12-cycle (C) induction phase with sc M plus Z (C1–12). Patients achieving at least stable disease (SD) after induction will continue with a 12-month maintenance phase of Z monotherapy (C13–24). The trial includes an initial safety run-in (SRI) phase comprising the first 10 patients monitored from Cycle 1 Day 1 (C1D1) through Cycle 3 Day 28 (C3D28) to assess early safety signals. Enrollment was then paused until SRI analysis is completed. Detailed information on dosing, study design, endpoints, and planned analyses has been previously presented (Ladetto, ASH 2024). Results Between Oct 23,2024 and Jan 10, 2025, 10 pts were enrolled; by May 1,2025 all had completed the SRI phase and were evaluable for safety. All pts were Caucasians, with a median age of 59 yrs (45–72) and a male-to-female (M/F) ratio of 4:6. All pts had an ECOG PS 0-1. Seven pts (70%) were at first relapse while three (30%) pts were at second relapse; two pts (20%) experienced progression of disease within 24 months (POD24). During the period from Cycle 1 Day 1 (C1D1) to Cycle 3 Day 28 (C3D28), No fatal grade (G) 5 or G4 adverse events (AEs) occurred and only one G3 neutropenia was reported during C3 and was successfully managed with G-CSF, with no subsequent complications. A total of 31 G1-2 AEs were recorded over 30 cycles including 4 cytokine release syndrome (CRS) events (three G1 and one G2). The median time to CRS onset was 1 day (1-2) after C1D1, and the median CRS duration was 1 day (1–3) and all resolved without sequelae. Only one pt, with G2 CRS, required tocilizumab and was cautiously hospitalized, resulting in the only SAE of the cohort. The most relevant G1–2 AEs included general disorders (four G1 non-CRS FUO, one G1 edema), cutaneous events (three G1 desquamation, one G2 erythema), vascular (two G1 hematomas), and gastrointestinal (one G2 diarrhea and one dyspepsia). No febrile neutropenia or ICANS occurred. Of the AEs, 59% (13) were related to M and 34% (11) to Z. No AEs led to drug withdrawal. One patient had M dose delays, and one temporarily stopped Z due to poor compliance. To date, all pts remain on treatment without any signs of PD. Among the 9/10 early response-evaluable pts (one pt is ongoing), all achieved a response and 7 achieved CR. Based on the results of the SRI analysis, the trial was re-opened for enrollment to complete the accrual of the planned 56 patients. Conclusion In this SRI, M plus Z showed an excellent safety profile without unexpected toxicities. CRS events were mostly low grade and resolved promptly. Preliminary efficacy is encouraging and overall data supports further study of this regimen in R/R FL. RT and ML share first authorship