Subcutaneous Mosunetuzumab Leads to High Rates of Durable Responses, Low Rates of Cytokine Release Syndrome, and Non-Inferior Exposure Compared with Intravenous Administration in Patients with Relapsed/Refractory Follicular Lymphoma: Primary Analysis of a Pivotal Phase II
Authors: Bartlett Nancy L. , Sehn Laurie H. , Assouline Sarit E. , Giri Pratyush , Kuruvilla John , Schuster Stephen J. , Yoon Sung-Soo , Fay Keith , Hess Georg , Dreyling Martin , Gutierrez Norma C. , Cybulski Eva , Kwan Antonia , Penuel Elicia , Tracy Samuel , Kuruvilla Denison , Chen Joseph , Wiebking Volker , Wei Michael C. , Budde L. Elizabeth 
Published: December 2024

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody approved by the FDA and EMA for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥2 prior lines of therapy by intravenous (IV) administration. In a Phase II study (NCT02500407), fixed-duration Mosun IV had a manageable safety profile and induced a high rate of complete responses (CRs; 60%) in patients (pts) with R/R FL (Budde et al. Lancet Oncol 2022). A subcutaneous (SC) formulation of Mosun, aimed at further improving safety and pt convenience, is currently under evaluation. Here we present data from the primary analysis of Mosun SC in pts with R/R FL.
Methods: Eligible pts had R/R FL Grade (Gr) 1-3a and ≥2 prior therapies. Mosun was administered by a single SC injection (≤1mL over 30s-2min) in 21-day cycles with step-up dosing in Cycle (C)1 (C1 Day [D]1, 5mg; C1D8, 45mg; C1D15, 45mg; C2D1 and onwards, 45mg). Corticosteroid prophylaxis was required during C1; hospitalization was not mandatory. Pts with a CR by C8 completed treatment; those with a partial response or stable disease continued therapy for up to 17 cycles. The primary objective was pharmacokinetic non-inferiority (PKNI) of Mosun SC to Mosun IV (historical control); co-primary pharmacokinetic (PK) endpoints were serum Ctrough(C3) and model-predicted cumulative serum AUCD0-84. Non-inferiority was defined as lower bounds of the 90% confidence interval (CI) of geometric mean ratios (GMRs) being above the pre-defined margin of 0.8. Secondary endpoints included overall response rate (ORR), CR rate, duration of response (DOR) and of CR (DOCR), progression-free survival (PFS), and overall survival (OS).
Results: Between Apr 2021 and Feb 2023, 94 pts were enrolled.At data cut-off (Feb 1, 2024), median time on study was 20.7 months (range: 1-34). Median age was 65 years (range: 35-84), 87% had Ann Arbor stage III/IV disease, and 56% had FLIPI score ≥3 at study entry. Median number of prior therapy lines was 3 (range: 2-9); 44% had progressive disease (PD) within 24 months from start of first-line therapy; 63% and 67% were refractory to their last therapy and any prior anti-CD20 therapy, respectively; 46% were double refractory to any prior anti-CD20 therapy and alkylating agent. Median number of cycles received was 8 (range: 1-17).
The PKNI analysis included 68/94 SC (only pts treated with updated drug formulation) and 90/90 IV PK-evaluable pts. The co-primary PK endpoints were met, with 90% CI lower bounds of the GMRs above 0.8 for both Ctrough(C3) (GMR 1.39 [90% CI: 1.2-1.6]) and AUCD0-84 (GMR 1.06 [90% CI: 0.9-1.2]).
In the Mosun SC group (n=94), ORR and CR rate (IRC-assessed) were 74% and 59%, respectively. Estimated 18-month DOR and DOCR were 60% (95% CI: 45.8-73.3) and 66% (95% CI: 51.0-80.2), respectively. Median PFS was 18.5 months (95% CI: 12.9-24.0); median OS was not reached.
Most common all-grade adverse events (AEs) were injection-site reactions (ISRs; 61%), fatigue (35%), and cytokine release syndrome (CRS; 30%). ISRs were all Gr 1/2 and non-serious; none led to treatment discontinuation. CRS events (Gr 1/2 28%; Gr 3 2%) were manageable; serious CRS events occurred in 15% of pts. All CRS events occurred in C1, mostly on C1D1 and C1D8; all resolved. Median time to CRS onset was 2.5 days; median duration was 2 days. Of 28 pts with CRS, 8 received tocilizumab and 6 received steroids. Suspected immune effector cell-associated neurotoxicity syndrome occurred in 3 pts (lethargy, n=2; memory impairment, n=1), with 2 events concurrent with CRS. All events were Gr 1, occurred during C1, and resolved without steroid use. Gr 3/4 and serious AEs were reported in 49% and 39% of pts, respectively. Mosun-related AEs led to treatment discontinuation in 3 pts. Gr 5 AEs (excluding PD) were reported in 5 pts (COVID-19 pneumonia, n=2; COVID-19, n=1; hemophagocytic lymphohistiocytosis, n=1 [with active Epstein-Barr virus, cytomegalovirus, and lymphoma transformation]; general physical health deterioration, n=1).
Conclusions: The study's co-primary PK endpoints were met, demonstrating non-inferior PK for Mosun SC vs Mosun IV. Fixed-duration Mosun SC achieved high rates of deep and durable responses in pts with R/R FL and ≥2 prior lines of therapy. The safety profile was manageable, with low CRS incidence and severity. Mosun SC potentially enhances pt convenience and practice efficiency, and can be delivered in an outpatient setting.