Mosunetuzumab Monotherapy Demonstrates Encouraging Activity and a Manageable Safety Profile in Patients with Heavily Pre-Treated Relapsed or Refractory Mantle Cell Lymphoma
Bibliographic record
Abstract
Background: New treatment options are needed for patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially those with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate B cells, including those that cause malignant disease. In a Phase I/II study (NCT02500407), mosunetuzumab demonstrated durable remissions with a manageable safety profile in pts with R/R B-cell non-Hodgkin lymphoma, including those with R/R MCL (Budde et al. J Clin Oncol 2024). Here we report the first efficacy and safety data from an expansion cohort for mosunetuzumab monotherapy at the recommended Phase II dose in pts with MCL who are R/R to BTKi therapy. Methods: Eligible pts with MCL, R/R to ≥1 prior regimen containing a BTKi, 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). Hospitalization was not mandatory. Pts with a complete response (CR) by C8 discontinued treatment; those with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoints were safety and tolerability. Efficacy was a secondary endpoint and was assessed by investigators according to Cheson 2007 criteria. Cytokine release syndrome (CRS) events were graded using the ASTCT criteria. Results: As of May 13, 2024, 25 pts were enrolled. Median age was 70 years (range: 50-89), 92% of pts had Ann Arbor stage III/IV disease, 64% had ECOG performance status 1, and 84% had MCL International Prognostic Index (MIPI) score ≥6. Median number of prior therapies was 3 (range: 2-6). All pts had ≥2 prior therapies, 80% had ≥3 prior therapies; 32% had a prior autologous stem cell transplant; 72% and 96% were refractory to a prior anti-CD20 therapy and a prior BTKi, respectively; 92% were refractory to their most recent regimen. Median number of mosunetuzumab cycles was 5 (range: 1-17), with 3 pts receiving >8 cycles. Median duration of follow-up for overall survival (OS) was 54.5 months. The best overall response rate (ORR) and CR rate were 44% and 24%, respectively. Median duration of response was 10.3 months (95% confidence interval [CI]: 2.3-19.5); median duration of CR was 18.0 months (95% CI: 10.3-22.3). Median progression-free survival was 3.7 months (95% CI: 1.4-5.8) and median OS was 7.3 months (95% CI: 3.6-25.9). The ORR and CR rate were consistent in pts with MIPI ≥6 (n=21; ORR 43%, CR 24%); additional subgroup efficacy analyses based on Ki-67 proliferation index and blastoid/pleomorphic morphology will be presented. The most common adverse events (AEs) were CRS (52%), fatigue (36%), and pyrexia (36%). CRS events were predominantly Grade (Gr) 1/2 (48%); Gr 3 CRS occurred in 1 pt; no Gr ≥4 CRS events were reported. CRS events occurred only in C1 and all events resolved. The median duration of CRS was 3 days (range: 1‒7). In pts with CRS, 4 (31%) received tocilizumab. Suspected immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred in 3 pts (Gr 1 confusional state [n=2]; Gr 2 delirium [n=1]); 2 events occurred concurrently with CRS. All events occurred early (C1 and C2) and resolved without steroid use. Gr 3/4 AEs were reported in 19 (76%) pts; Gr 3/4 AEs occurring in ≥10% of pts included neutropenia (28%; no febrile neutropenia), hypophosphatemia (20%), thrombocytopenia (16%), and anemia (12%). Serious AEs (excluding fatal PD) occurred in 14 (56%) pts; 10 (40%) were treatment related. No Gr 5 AEs were reported (excluding PD). An AE leading to treatment discontinuation occurred in 1 pt (subdural haematoma; unrelated to mosunetuzumab). Conclusions: Fixed-duration mosunetuzumab demonstrated encouraging single-agent activity in a challenging-to-treat population of pts with high-risk and refractory MCL. The safety profile was manageable, characterized by predominantly low-grade CRS events confined to C1, all of which resolved. Mosunetuzumab's tolerability, off-the-shelf availability, lack of mandatory hospitalization, and convenient dosing schedule provide rationale for further exploration in this setting. Currently, mosunetuzumab is being investigated in combination with polatuzumab vedotin for pts with R/R MCL (NCT03671018).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".