Mosunetuzumab Plus Polatuzumab Vedotin Demonstrates a Favorable Safety Profile and Efficacy in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Primary Analysis of a Phase Ib/II Study
Authors: Budde L. Elizabeth , Olszewski Adam J , Assouline Sarit , Lossos Izidore S. , Diefenbach Catherine , Kamdar Manali , Ghosh Nilanjan , Modi Dipenkumar , Sabry Waleed , Naik Seema , Mehta Amitkumar , Nakhoda Shazia K. , Smith Stephen D , Dorritie Kathleen , Jia Ting , Pham Song , Huw Ling-Yuh , Wu Hao , To Iris , Wei Michael C. , Chavez Julio C. 
Published: December 2023

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. The ongoing Phase Ib/II GO40516 study (NCT03671018) investigates Mosun in combination with polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). The Phase II expansion phase of the M-Pola regimen (with conventional Mosun and Pola dose and dose schedule), showed an acceptable safety profile and promising anti-tumor activity in pts with R/R B-NHL at interim analysis (Budde et al. ASH 2021). With enrollment complete, we present full dose-expansion cohort results.
Methods: Eligible pts had confirmed R/R LBCL (including diffuse LBCL not otherwise specified, high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma [tFL], and follicular lymphoma [FL] grade [Gr] 3b) and had received ≥1 prior line of therapy (including an anti-CD20 antibody). Treatment cycles were 21 days. Pola (1.8mg/kg; intravenous [IV]) was administered on Day (D) 1 of Cycles (C) 1-6. Mosun IV was administered with C1 step-up dosing to mitigate cytokine release syndrome (CRS), with the following dose and dose schedule: 1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3+. Pts with a complete response (CR) completed Mosun after C8, and pts with stable disease or partial response at the end of C8 continued Mosun for a total of 17 cycles. Primary endpoint was best overall response rate (ORR) by independent review committee (IRC) using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019).
Results: As of April 7, 2023, 98 pts received M-Pola in the dose-expansion cohort. Median age was 68.0 years (range: 20-88), 71.4% were male, 87.8% had de novo DLBCL, 8.2% had tFL, 4.1% had Gr 3b FL, 18.4% had HGBCL (including double/triple-hit lymphoma), 7.1% had bulky disease (≥10 cm), 51.0% had an International Prognostic Index score 3-5, and 85.7% had Ann Arbor stage III/IV disease. The median number of prior lines of therapy was 2 (range: 1-8), 35.7% had prior CAR-T therapy, and 11.2% had prior ASCT. Most pts (80.6%) were refractory to prior anti-CD20 therapy, 58.2% were primary refractory, 77.6% were refractory to their previous therapy, and 26.5% were refractory to CAR-T therapy. The median number of cycles received was 8 for Mosun (range: 1-17) and 6 for Pola (range: 1-6).
Adverse events (AEs) occurring in ≥15% of pts were fatigue (42.9%), neutropenia (28.6%), nausea (26.5%), diarrhea (23.5%), pyrexia (23.5%), headache (21.4%), CRS (18.4%), chills (17.3%), and peripheral sensory neuropathy (16.3%). Gr 3/4 AEs that occurred in ≥5% pts were neutropenia (20.4%) and fatigue (7.1%). Gr 5 AEs occurred in 3 (3.1%) pts, of which 2 were due to COVID-19 pneumonia and 1 was due to pneumonia. None were considered related to treatment. CRS events were observed in 18.4% of pts: Gr 1 n=11, Gr 2 n=4, Gr 3 n=3. All CRS events were resolved by data cut-off. Three pts received tocilizumab, 2 pts had a vasopressor, 2 pts received high flow oxygen, and 2 pts required ICU admission for CRS. Mosun-related neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 5 pts (5.1%); all were Gr 1/2 except 1 Gr 4 encephalopathy event. Treatment-related neuropathy occurred in 25.5% of pts (all Gr 1/2). Eleven pts (11.2%) discontinued treatment due to AEs, of which 5 (5.1%) were treatment-related: 1 (1.0%) due to encephalopathy (Mosun-related) and 4 (4.1%) due to peripheral neuropathy (Pola-related).
Investigator-assessed ORR and CR rate were 62.2% and 50.0%, respectively ( Table). Median duration of response was not reached (NR; 95% confidence interval [CI]: 11.6-NR); median duration of CR was NR (95% CI: 20.5-NR). Median progression-free survival was 9.6 months (95% CI: 5.6-18.6) and overall survival was 23.3 months (95% CI: 15.2-NR), with a median follow-up of 18.6 months (95% CI: 17.7-23.7). In pts with prior CAR-T therapy (n=35), the ORR and CR rates were 60.0% and 45.7%, respectively. In primary refractory pts (n=57), the ORR and CR rates were 56.1% and 40.4%, respectively.
Conclusions: M-Pola continues to show a favorable safety profile and compelling efficacy in highly refractory pts, including those with prior CAR-T therapy and/or primary refractory disease. Primary analysis data, including IRC responses and biomarker analyses, will be presented.