Combined mosunetuzumab and zanubrutinib for the treatment of patients with newly diagnosed high-burden follicular lymphoma: First results of the multicenter phase 2 mithic-FL2 trial

Abstract

Abstract Introduction: Chemotherapy-free, bispecific antibody (BsAb)-containing therapies have the potential to challenge the role of standard chemoimmunotherapy as frontline treatment of patients (pts) with follicular lymphoma (FL) in need of systemic therapy. In the multicenter phase 2 MITHIC-FL1 trial subcutaneous (SC) mosunetuzumab produced high complete response (CR) rates with manageable adverse events (AE) (Falchi et al. ASH 2024). Zanubrutinib is a second-generation BTK inhibitor with direct anti-FL activity and the potential ability to correct defective T-cell function, which may synergistically enhance BsAb-mediated tumor-killing. Here, we present the first results of MITHIC-FL2, a multicenter phase 2 trial of mosunetuzumab with zanubrutinib in patients with previously untreated FL. Methods: Key eligibility criteria included: Age ≥18 y, ECOG PS 0-2, biopsy-proven CD20+, grade 1-3A FL, stage 2-4, need for therapy per GELF criteria. SC mosunetuzumab was administered on a step-up dosing schedule in cycle (C)1 (5 mg on day [D]1, 45 mg on D8 and 45 mg on D15), then at 45 mg on D1 every 21 days for up to 8 Cs (if CR was achieved) or 17 Cs (if partial response [PR] was achieved). Zanubrutinib was administered orally at the dose of 320 mg daily or 160 mg twice daily starting on C1D-7 and continued daily for 12 months. Premedication with single-dose dexamethasone, diphenhydramine, and acetaminophen was mandatory before each mosun dose in C1 (and C2 if cytokine release syndrome (CRS) occurred in C1), optional thereafter. Treatment was administered on an outpatient basis. The primary endpoint was complete response (CR) rate at the end of study therapy. Response was assessed following the Lugano 2014 criteria, complemented by the LYRIC criteria. Cytokine release syndrome (CRS) and neurological adverse events (AE) were graded according to the 2019 ASTCT criteria. Results: Between August 2024 and July 2025, 47 pts were enrolled and 45 pts received ≥1 dose of study drug and are safety evaluable. The median age was 59 years (range 33-79), 40% of pts had bulky disease (≥7 cm), 20% had grade 3A FL, and 18% had a FLIPI score ≥3. The median baseline SUVmax was 11.8 (range 5.6-33.6). As of the July 1, 2025 cutoff date, 40 pts remained on treatment; 2 pts discontinued early due to biopsy-confirmed progression (PD), 1 due to stable disease (SD) per physician discretion, 1 due to AE, and 1 discontinued on C1D8 due to later finding of diffuse large B-cell lymphoma on pre-treatment bone marrow biopsy. At a median follow up of 3.8 months, pts have received a median of 6 mosunetuzumab cycles (range 1-10) and 4.2 months of zanubrutinib treatment (range 0.1-10.5). Out of 232 mosunetuzumab patient-cycles administered, 10 (4%) were delayed due to AEs by a median of 7 days (range 4-21). Five pts experienced zanubrutinib dose interruptions due to AE, lasting ≤7 days in 3 of them. Among 45 safety-evaluable pts, the most common (≥20%) treatment-emergent AE were injection site reactions (62%), CRS (56%), dry skin (53%), infections (29%), fatigue (27%), and skin rash (27%); all of these events were G1-2. Bruising/bleeding occurred in 15% of pts, all G1. CRS occurred mostly after C1D1 and was either G1 (21/25 pts, 84%) or G2 (4/25 pts 16%). G≥3 AEs included neutropenia (2 pts, 4%), anemia (1 pt, 2%), and LFT elevation (1 pt, 2%). One pt had G3 vasovagal syncope and another had G3 acute kidney injury due to ureteral obstruction caused by PD. One pt developed G5 EBV-associated hemophagocytic lymphohistiocytosis during Cycle 1. This pt had negative EBER staining on baseline biopsy and did not have detectable EBV viral load at baseline. No neurotoxicity, clinical TLS, or atrial fibrillation were seen. Thus far, 27 pts are evaluable for response. The best overall response rate is 85% (23/27) and the metabolic CR rate is 74% (20/27); 2 pt had SD, and 2 pts had PD. At a median follow-up for response-evaluable pts of 5.1 months, no pt with an objective response has progressed. Conclusion: We report the first study of combined zanubrutinib and mosunetuzumab in pts with previously untreated high-burden FL. AEs were manageable and the safety profile was as expected for the individual agents, with no new safety signals observed. Most patients achieved a complete metabolic response. The study continues to enroll and updated data will be presented.