Glofitamab Induces High Response Rates and Durable Remissions in Patients (Pts) with Heavily Pretreated Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL), Including Those with a Poor Prognosis: Subgroup Results from a Phase I/II Study

Background: Pts with R/R MCL continue to have a poor prognosis, especially those whose disease has become R/R to Bruton tyrosine kinase inhibitor (BTKi)-containing therapies. Additional treatments are needed for pts with R/R MCL. Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody that is approved for the treatment of pts with R/R diffuse large B-cell lymphoma who have received ≥2 prior lines of therapy. In an ongoing Phase I/II study (NP30179; NCT03075696), fixed-duration glofitamab monotherapy induced high response rates and durable remissions, and had a manageable safety profile, in heavily pretreated pts with R/R MCL (Phillips et al. ASCO 2024). We report updated results for the R/R MCL cohort, including efficacy in clinically and/or histologically defined high-risk subgroups, as well as initial analysis of minimal residual disease (MRD). Methods: Eligible pts were those with R/R MCL who had received ≥1 prior line of therapy. All pts received obinutuzumab pretreatment (1000mg or 2000mg) on Cycle (C) 1 Day (D) 1. Glofitamab was then given as step up doses on C1D8 (2.5mg) and C1D15 (10mg) and at the target dose (16mg or 30mg) on D1 of each subsequent cycle (C2-12). Investigators assessed the tumor response using Lugano 2014 criteria. Formalin-fixed paraffin-embedded tumor biopsies were classified as classical, blastoid or pleomorphic and analyzed by immunohistochemistry for Ki-67 or p53 expression. MRD was evaluated in genomic or plasma DNA by clonoSEQ. Results: As of May 17, 2024, 60 pts received treatment (safety population; median age: 72 years, range: 41-86). Most pts (86.7%) had Ann Arbor stage III or IV disease at entry. The median number of prior lines of therapy was 2 (range: 1-5); 46.7% of pts had received ≥3 prior therapies and 55.0% had received ≥1 prior BTKi therapy. The majority of pts (73.3%) were refractory to their last prior therapy and 51.7% were refractory to any prior BTKi. Among pts with an evaluable baseline biopsy, 53.0% (25/46) had ≥1 high-risk histological feature, defined as blastoid morphology, Ki-67 expression >50% or p53 expression >50%. Median overall survival (OS) follow-up was 24.2 months (range: 0-50) at cut-off. In the intent-to-treat population of all enrolled pts (N=61), the overall response rate was 82% and complete response (CR) rate was 77%. Median time to response was 42 days (range: 29-164) and median duration of CR (DOCR) was 46.5 months (range: 1-47), with 57.4% of complete responders still in response at cut-off. Median progression-free survival (PFS) was 18.0 months (95% CI: 11.3, not estimable [NE]) and median OS was NE (95% CI: 21.6, NE). Response rates were consistent in patient subgroups defined by baseline clinical characteristics. CR rates were: 76% and 78% in those aged <70 (n=25) and ≥70 (n=36) years; 80%, 78%, and 75% in those with 1 (n=15), 2 (n=18) and ≥3 (n=28) prior lines of therapy; 71% and 85% in those with (n=34) and without (n=27) prior BTKi exposure; and 76% and 81% in those who were (n=45) and were not (n=16) refractory to their last prior therapy, respectively. Among pts with an evaluable baseline biopsy, CR rates were 68.0% and 81.0% in those with (n=25) and without (n=21) ≥1 high-risk features. In detail, CR rates were: 60% and 73% in those with (n=5) and without (n=37) blastoid morphology; 68% and 78% in those with (n=19) and without (n=27) Ki-67 expression >50%; and 67% and 76% in those with (n=9) and without (n=37) p53 expression >50%. Median DOCRs in those with or without ≥1 high-risk features were 21.5 months (95% CI: 17.7, NE) and 19.2 months (95% CI:17.4, 42.8), respectively. Landmark analyses indicated that most pts who were in CR at end of treatment (EOT) were progression free and alive at 18 months after EOT (PFS rate: 71.8%; OS rate: 83.0%). A trackable MRD clone was identified in 17/31 (54.8%) pts in CR at EOT. Among these pts, 11/12 (91.6%) with evaluable samples had undetectable MRD at C3. Exploratory data on B-cell recovery and Ig levels after EOT will be presented. No new or unexpected safety signals were reported. Conclusions: Glofitamab induces high response rates in pts with heavily pretreated R/R MCL, including those who have clinical and/or histological features associated with poor prognosis. Clinical and molecular remissions are achieved early in the course of treatment, with durable responses lasting beyond the length of the treatment.

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