Single-Agent Mosunetuzumab Produces High Complete Response Rates in Patients with Newly Diagnosed Follicular Lymphoma: Primary Analysis of the Mithic-FL1 Trial

Introduction: Chemotherapy-free, CD20xCD3 bispecific antibody-based therapies are challenging the role of standard 1st line (1L) chemoimmunotherapy for patients (pts) with follicular lymphoma (FL) (Falchi et al. ASH 2023; Falchi et al. EHA 2024). In a preliminary report of a multicenter phase 2 trial of 1L subcutaneous (SC) mosunetuzumab (mosun) for high-burden FL we showed high complete response (CR) rates and manageable adverse events (AE). Here, we present the results of the primary analysis of the fully accrued trial. Methods: The following eligibility criteria were to be met: Age ≥18 y, ECOG PS 0-2, biopsy-proven CD20+, grade 1-3A FL, stage 2-4, requiring therapy per GELF criteria. SC mosun was administered on a step-up dosing schedule in cycle (C)1 (5 mg on day [D]1, 45 mg on D8 and 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). 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. Response was assessed following the Lugano 2014 criteria. CRS and neurological AE were graded according to the 2019 ASTCT criteria. Results: Between June 2022 and July 2024, 78 pts were enrolled. The median age was 59 y (range, 26 - 83), 77% of pts were Caucasian, 13% Asian, 3% Black, and in 7% race was unknown; 4% were Hispanic. 36% had bulky disease, 19% had grade 3A FL, and 24% had FLIPI score ≥3. The median baseline SUVmax was 11.7 (range 3.7 - 41.1). The median time from diagnosis to C1D1 was 3.5 months (range 0.3 - 145.7). At the cutoff date of 7/29/24, 62 patients have completed therapy, 10 are receiving treatment, and 6 discontinued prematurely due to progressive disease (PD; 1), AE (4, 1 related to study drug), or physician decision (1). The most common (>20%) treatment-emergent AEs were injection site reactions (69%, 53 G1 and 1 G2), CRS (54%), infections (54%, 40 G1-2 and 2 G3), skin rash (47%), musculoskeletal pain (38%), dry skin (37%), fatigue (35%). Notable G≥3 AEs include neutropenia (18%), febrile neutropenia (4%). Of the 60 CRS events, 95% were G1 and 5% were G2; 93% of the episodes occurred during C1. Hospitalization and tocilizumab were only required in the two pts with G2 CRS and all events resolved fully. No patient had neurotoxicity. Two pts discontinued treatment before response evaluation due to unrelated AE (second cancer and bowel perforation). Among the 76 efficacy evaluable patients, the best overall response rate is 95% (95% CI: 87-99%) and the CR rate is 80% (95% CI: 70-89%). The vast majority of CR (54/61, 89%) were seen at the first assessment (4 cycles). Of the 9 pts with PR at cycle 8, 7 completed 17 cycles and 2 have not yet completed therapy. Among pts completing 17 cycles, 3 converted to CR (2 by cycle 17 and 1 3 months thereafter), and 4 remained in PR and either received radiation to a single site of residual disease (2) or were observed (2). No baseline characteristic, including FLIPI, bulk, or SUVmax, correlated with the likelihood of CR in univariate analysis. At a median follow up of 10.6 months (range, 1.4 - 25.3+), 6 pts have experienced progression (PD), 3 of them with CD20 loss. The median progression-free survival (PFS) is not reached. At 12 months, the estimated PFS probability is 88% (95% CI: 79% - 98%). Among the 6 pts with PD, 3 have required therapy so far, while 3 are being observed at 16.5, 10.5, and 4.5 months from the time of PD. 2 pts experienced transformation to diffuse large B-cell lymphoma, one found 6 weeks after C1D1 in a lymph node with baseline SUVmax 41, the other 3 months after therapy completion. At a median follow up for complete responders of 8.7 months, the estimated probability of remaining in CR at 12 months is 89% (95% CI: 80% - 100%). Two patients have died: A cardiac arrhythmia in the setting of COVID19-associated pneumonia and a sudden cardiac death occurring 4 months and 20 months, respectively, after study initiation. The estimated 12-month OS rate is 99% (96 - 100%). Conclusion: In pts with newly diagnosed high-burden FL, fixed-duration, outpatient SC mosun showed remarkable efficacy, with CR rates comparable to those seen with chemoimmunotherapy, and most patients maintaining their response. AE were manageable, without new safety signals. Our data support further evaluation of this off-the-shelf drug as 1L therapy for high-burden FL.