Mosunetuzumab in Combination with Lenalidomide Has a Manageable Safety Profile and Encouraging Activity in Patients with Relapsed/Refractory Follicular Lymphoma: Initial Results from a Phase Ib Study

Background: Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain an unmet need population. Monotherapy with mosunetuzumab (M), a CD20xCD3 bispecific antibody, has demonstrated high and consistent response rates in high-risk R/R FL subsets, with early evidence of response durability and a favorable benefit/risk profile (Assouline et al. ASH 2020). Lenalidomide (Len) is clinically active in pts with FL, and its potent immunomodulatory activity offers the potential for additive/synergistic efficacy when combined with M. Here, we present initial data from an ongoing Phase Ib study (NCT04246086) evaluating the safety and activity of M+Len in R/R FL pts who have received at least one prior line of therapy.

Methods: Pts with R/R FL (Grade [Gr] 1-3a) and at least one prior systemic anti-cancer therapy were enrolled to receive 12 cycles of M+Len (cycle duration: Cycle [C] 1, 21 days; C2-12, 28 days). In C1, step-up doses of M (IV infusion) are given on C1 Day (D)1 (1mg) and C1D8 (2mg), with the target dose given on C1D15 (30mg) and on D1 of C2-12. Len (20mg orally) is administered on D1-21 of C2-12. No hospitalization is mandated by the protocol. The primary objective is to evaluate the safety of M+Len; secondary objectives include assessment of response and long-term efficacy outcomes. Cytokine release syndrome (CRS) is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014).

Results: At data cut-off (May 31, 2021), 27 pts had been enrolled. Median age was 59 years (range: 31-79 years); 12 pts (44%) were male. All pts had an ECOG performance status of 0 (18 pts, 67%) or 1 (9 pts, 33%). Median number of prior lines of therapy was 1 (range: 1-4), and 3 pts (11%) had disease progression (PD) <24 months from the start of first-line therapy. At data cut-off, 16 pts (59%) had been on study for 0-3 months, 8 (30%) for 3-6 months, 2 (7%) for 6-9 months, and 1 for >9 months.

All 27 pts were safety evaluable at data cut-off. Twenty pts (74%) experienced ≥1 adverse event (AE) of any Gr; the most common AE was CRS (8 pts, 30%). Gr 3-4 AEs occurred in 8 pts (30%) and serious AEs in 8 pts (30%). No Gr 5 (fatal) AEs were observed. AEs relating to M occurred in 20 pts (74%) and AEs relating to Len occurred in 10 pts (37%). There were no AEs leading to withdrawal of M or Len; 2 pts had M-related AEs leading to M dose delays, 6 pts (22%) had Len-related AEs leading to Len dose interruption and/or reduction. In all pts, CRS events were Gr 1 (7/8 pts) or Gr 2 (1/8 pts). For most pts (6/8), CRS events occurred C1D1-C1D7; 2 pts experienced Gr 1 CRS events in C2. Median time to CRS onset was 1 day after first study drug administration (range: 1-28 days), median CRS duration was 3 days (range: 2-5 days). All CRS events resolved without sequelae. No pt required tocilizumab, ICU admission, high flow oxygen, or vasopressor support. Five pts (19%) reported 14 events of Gr 3-4 neutropenia; all neutropenia events occurred between D41 and D218, with a duration of 6-16 days. All neutropenia events resolved, with 1 patient receiving primary G-CSF prophylaxis and 2 pts receiving G-CSF treatment. No febrile neutropenia events occurred.

The efficacy-evaluable population included all pts who had been assessed for response at any time on study, who had withdrawn from treatment or study prior to reaching their first response assessment, or who had been on study long enough to have reached their first scheduled response assessment, planned per protocol for D15-21 of C3. Objective response rate in the 13 pts who were efficacy evaluable at data cut-off was 92%, with complete metabolic response observed in 10 pts (77%), partial metabolic response (PMR) in 2 pts (15%), and stable disease in 1 patient (8%). One pt who initially achieved PMR experienced PD after 8 cycles of treatment.

Conclusions: M+Len appears to have an acceptable safety profile in pts with R/R FL who have received at least one prior line of therapy, with encouraging preliminary anti-lymphoma activity observed. These data support initiation of a randomized Phase III study of M+Len versus rituximab+Len. Updated safety, efficacy, and pharmacokinetic data will be presented at the meeting.