Mosunetuzumab with Response-Driven Lenalidomide Augmentation As First-Line Therapy for Symptomatic Follicular or Marginal Zone Lymphoma: Interim Analysis of a Multi-Center Phase 2 Study

Background: Mosunetuzumab (Mosun) is a bispecific CD20xCD3 antibody approved for the treatment of follicular lymphoma (FL) after ≥2 lines of therapy. In that setting, Mosun provides 60% complete response (CR) rate despite prior immunosuppressive therapy [Budde et al., Lancet Oncol 2022]. BrUOG-401 (NCT04792502) is an investigator-initiated, multicenter, single arm, phase 2 clinical trial testing the hypothesis that administering Mosun for previously untreated FL or marginal zone lymphoma (MZL) will result in a higher CR rate than standard chemoimmunotherapy. Additionally, selective immune augmentation using low-dose lenalidomide (Len) may improve response for patients who do not attain CR on interim assessment. Here, we present the pre-planned interim efficacy analysis of this trial.

Methods: Patients with previously untreated, high-burden or symptomatic FL or MZL received subcutaneous Mosun for 8 planned cycles (C) with step-up dosing in C1 (day 1: 5mg, day 8 & 15: 45 mg; then 45mg on day 1 of C2-C8). Patients who attained only partial response [PR] or stable disease at interim assessment after C4 received the addition of Len augmentation (10mg daily, continuously) during C5-C8, with an optional extension up to C12. The primary endpoint is the CR rate at the end of therapy, assessed using PET-CT-based Lugano criteria [Cheson et al., JCO 2014]. However, for the primary hypothesis evaluation, we used CT-based criteria to test the superiority of the CR rate over the historical 53% CR rate reported (using CT criteria only) with bendamustine/rituximab chemotherapy in the RELEVANCE trial (Morschhauser et al., NEJM 2018). This pre-planned interim analysis occurred after 25 patients were evaluable for response, with futility stopping rule if ≤13 CR’s were observed. Secondary objectives include safety, overall response rate (ORR), progression-free and overall survival (OS), as well as the rate of conversion from PR to CR on Mosun+Len augmentation. Adverse events (AE) were graded using CTCAE v5 criteria, and cytokine release syndrome (CRS) using the 2019 ASTCT criteria.

Results: As of July 2024, 37 patients (median age 65, range 30-89; 58% women; 86% white non-Hispanic) were enrolled, including 22 (59%) with FL and 15 (41%) with MZL. The lymphoma stage was 2 in 14%, 3 in 22%, and 4 in 64%. Among the FL patients, FLIPI was low in 6, intermediate in 7, and high in 9. Two patients discontinued treatment (1 for AE, 1 for progression) before completing C8.

The most common AE on treatment included injection site reaction (n=18 [49%]; grade [G]1 in 17, G2 in 1), fatigue (43%; G1/2 in 15, G3 in 1), and rash (38%; G1/2 in 11, G3 in 3). Other G3/4 AE’s (in ≥2 patients) included Pneumocystis jirovecii pneumonias (PJP, occurred during C2 and C3), hypertension, weakness, pain, and neutropenia (each in n=2). There were 6 (16%) CRS events, all G1 and during C1, and all resolved. One patient received tocilizumab. No G3/4 toxicities attributed to Len were observed.

At the data cutoff, 25 patients were evaluable for response. Using Lugano criteria, the CR rate was 82% (95% confidence interval [CI], 60-95%), and the ORR was 86% (95%CI, 65-97%). The CR rate was 80% for FL and 86% for MZL. Six patients received Len augmentation and 3 of the evaluable 4 converted to CR, whereas one had (after initial PR) progressive disease with biopsy-proven histologic transformation. With short follow up (median 5.8 months), no recurrence was observed among patients with CR; OS is 100%. The 14 observed CR’s (using CT-based criteria) satisfied the interim analysis criterion for the pre-planned two-stage design.

Flow cytometry demonstrated, apart from a rapid B-cell depletion, a temporary decrease in circulating TEMRA CD8+ T-cells and a significant increase in LAG3 and PD-1 expression at C2. At the end of C4, patients not attaining early CR showed significantly lower counts of NK cells (P=0.009) and no effector memory T-cell expansion. These differences resolved after 4 cycles of Mosun+Len augmentation.

Conclusions: Fixed-duration subcutaneous Mosun resulted in a high CR rate during first-line treatment of FL and MZL with limited toxicity, including only 16% rate of G1 CRS, and similar CR rates in FL and MZL on this initial assessment. Selective immune augmentation using low-dose continuous Len was safe and may facilitate conversion to CR for slow early responders. Study enrollment continues and both safety and efficacy analyses with longer follow-up will be presented.