Mosunetuzumab Continues to Demonstrate Clinically Meaningful Outcomes in Patients with Relapsed and/or Refractory Follicular Lymphoma after ≥2 Prior Therapies Including Those with a History of POD24: 4-Year Follow-up of a Pivotal Phase II Study

Background: Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved by the FDA and EMA for the treatment of relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy. In a pivotal Phase II study (NCT02500407), mosunetuzumab demonstrated high overall and complete response rates (ORR and CR) with a manageable safety profile in patients with R/R FL (Budde et al. Lancet Oncol 2022). Durable responses were observed after 3 years of follow-up, including in patients with a history of disease progression within 24 months from the start of first-line therapy (POD24; Schuster et al. ASH 2023; Assouline et al. EHA 2024). Here we present updated data after 4 years of follow-up.

Methods: Eligible patients with R/R FL Grade (Gr) 1–3a and ≥2 prior therapies were enrolled. Mosunetuzumab was administered intravenously in 21-day cycles with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1mg; C1D8, 2mg; C1D15/C2D1, 60mg; C3D1 and onwards, 30mg). Patients with a CR by C8 completed treatment without additional cycles; those with a partial response or stable disease (SD) continued treatment for up to 17 cycles. Hospitalization was not mandatory. The primary endpoint was CR rate as best response determined by an Independent Review Committee (Cheson 2007 criteria). Secondary endpoints included duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), and safety. Follow-up response assessments were performed by investigators. Post-hoc analyses were performed for patients with or without POD24. Long-term safety was analyzed, including rates of serious infections after end of treatment (EOT).

Results: Ninety patients with R/R FL were enrolled, of whom 47 (52.2%) had POD24. As of May 13, 2024, median time on study was 49.4 months. All patients either completed (63.3%) or discontinued (36.7%) treatment. Five patients whose disease relapsed after an initial CR received retreatment with mosunetuzumab.

The ORR and CR rates in the overall population were 77.8% and 60.0%, respectively. Median DOR and DOCR were 46.4 months (95% confidence interval [CI]: 18.7–not estimable [NE]) and 51.8 months (95% CI: 46.4–NE), respectively. Thirty-five (64.8%) patients with a CR remained in remission at 4 years. Median PFS was 24.0 months (95% CI: 12.0–NE) and the estimated 4-year PFS rate was 38.6% (95% CI: 27.1–50.2). Median OS was not reached, and the estimated 4-year OS rate was 82.7% (95% CI: 74.7–90.7). Of the 5 patients who received retreatment, 4 had a CR and 1 had SD following retreatment.

In patients with POD24, the ORR and CR rates were 80.9% and 59.6%, respectively. Median DOR was 46.4 months (95% CI: 10.6–NE) and median DOCR was 46.4 months (95% CI: 18.7–NE). Nineteen (67.9%) patients with a CR remained in remission at 4 years. Median PFS was 21.7 months (95% CI: 11.6–NE) and the estimated 4-year PFS rate was 38.9% (95% CI: 22.0–55.9). Median OS was not reached; the estimated 4-year OS rate was 86.4% (95% CI: 76.3–96.6).

No additional adverse events (AEs) were reported since the 3-year follow-up analysis. CRS remained the most common AE (all grades, 44.4%; Gr 1/2, 42.3%), occurring most frequently in C1. Serious infections were reported in 20.0% of patients, with no Gr 5 infections. Most serious infections (73.7%) occurred in the first 4 cycles. Among 69 patients who received at least 8 cycles of treatment, serious infections after C8 were reported in 3 (4.3%) patients. B-cell recovery to detectable levels was observed after a median of 19.0 months (95% CI: 12.8–25.1); immunoglobulin M recovery to the lower limit of normal was observed after a median of 40.7 months (95% CI: 36.1–NE).

Conclusions: In this updated analysis, fixed-duration mosunetuzumab continued to demonstrate durable benefit in patients with R/R FL. Nearly two-thirds of patients with a CR remained event-free after a median of 4 years of follow-up, and retreatment data were encouraging. Efficacy in patients with POD24 was consistent with the overall population. The safety profile was manageable and most serious infections occurred in early cycles. With >4 years of follow-up, the durable responses, absence of new AEs, immune recovery after EOT, and ability to retreat, support a fixed treatment duration approach with mosunetuzumab in patients with R/R FL. These results continue to support the evaluation of mosunetuzumab in earlier lines of therapy, as a single agent, and in combination.