Rationale for Requested Change: Please review the enclosed results of the Phase II trial for Lunsumio™ (mosunetuzumab-axgb) in combination with Polivy® (polatuzumab vedotin-piiq) for the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Results from the study were published in the journal Nature Medicine and presented at the 65th American Society of Hematology (ASH) Annual Meeting in December 2023.
Large B-cell lymphoma (LBCL) can be managed in the frontline setting with immunotherapy regimens that have a potential for cure.[1,2] However, despite these regimens, approximately 20–40% of patients are refractory or experience subsequent relapse with frontline therapy, resulting in an unmet need for effective therapies to improve outcomes for patients with R/R LBCL.[2,3] Both mosunetuzumab-axgb and polatuzumab vedotin have individually demonstrated promising activity in patients with relapsed or refractory (R/R) non-Hodgkin lymphoma.[4,5] There is evidence that mosunetuzumab combined with polatuzumab vedotin (mosun-pola) targets distinct components of malignant B-cell biology, and initial findings of this combination therapy have been presented.[6]
GO40516 (NCT03671018) is an ongoing open-label, multicenter study with a phase 2 single-arm expansion cohort of fixed-duration mosunetuzumab in combination with polatuzumab vedotin in patients with second-line or later R/R LBCL.[7] Hospitalization as a risk mitigation measure was not mandatory. Intravenous mosunetuzumab was administered at a step-up dose of 1/2/60/30 mg in 21-day cycles (C). Patients who achieved a complete response (CR) by C8 may stop mosunetuzumab treatment, while other patients may receive up to 17 cycles. Polatuzumab vedotin 1.8 mg/kg was administered for 6 cycles. The primary efficacy endpoint was best overall response rate (ORR) by Independent Review Committee (IRC) based on the Lugano 2014 criteria. Key secondary endpoints included best CR, duration of response (DoR), progression-free survival (PFS), and overall survival (OS).
Ninety-eight patients were enrolled and treated with mosun-pola. The median number of previous lines of therapy was 2 (range 1-8); 76 patients (77.6%) were refractory to their last previous therapy, 56 (57.1%) were primary refractory, 80 (81.6%) were refractory to any previous anti-CD20 therapy, and 35 (35.7%) received prior CAR-T, of which 26 (74.3%) were refractory.
Efficacy
At the data cutoff date of July 6, 2023, the median follow-up was 23.9 months (95% CI, 21.3-26.8).[7,8] The primary efficacy endpoint was met with a best ORR by IRC of 59.2% (95% CI, 48.8-69) vs the 42% historical control rate (p = 0.0003). INV-assessed best ORR was 63.3% (n=62; 95% CI, 52.9-72.8), best CR rate was 51% (n=50; 95% CI, 49.1-70.2).
The median duration of response (DOR) was 20.8 months (95% CI, 14-NE) and median duration of complete response (DoCR) was not reached (95% CI, 20.5-NR).[8] The median PFS was 11.4 months (95% CI, 6.2-18.7), and median OS was 23.3 months (14.8-NE). Durable responses were also seen among 35 patients with prior CAR T-cell therapy, with median DOR and DOCR not reached. Median PFS and OS were 9.6 months (95% CI, 4.9-NR) and 15.2 months (95% CI, 9.5-NR), respectively. Please refer to the figures in the cited manuscript and ASH presentation for KM plots by IRC, including PFS and OS.[7,8]
Safety
The most common adverse events (AEs) were fatigue (45.9%), neutropenia (29.6%), and diarrhea (24.5%). The most common Grade 3-4 AEs were neutropenia (20.4%) and fatigue (6.1%). Grade 5 events (n=3) included 2 patients (2%) with COVID-19 pneumonia and 1 patient (1%) with pneumonia.[7]
Cytokine release syndrome using the American Society for Transplantation and Cellular Therapy (ASTCT) 2019 criteria occurred in 18 patients (18.4%), was confined to C1, and predominantly low-grade (10 [10.2%] Grade 1, 5 [5.1%] Grade 2, and 3 [3.1%] Grade 3).[8] All CRS events resolved.
In the GO40516 study, mosunetuzumab in combination with polatuzumab induced durable responses with a median PFS of 11.4 months, median OS of 23.3 months, and median DoCR that was not reached with 23.9 months of median follow-up. This, paired with a manageable safety profile in R/R LBCL patients demonstrates mosun-pola as an effective treatment option for this area of high unmet need.
