Fixed-Duration Glofitamab Monotherapy Continues to Demonstrate Durable Responses in Patients with Relapsed or Refractory Large B-Cell Lymphoma: 3-Year Follow-up from a Pivotal Phase II Study

Background: Glofitamab is a CD20xCD3 bispecific antibody that engages and redirects T cells to eliminate B cells. In this Phase II study (NCT03075696) of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and durable responses with manageable toxicity (Dickinson, et al. N Engl J Med 2022). As a result, glofitamab monotherapy was approved by the FDA and EMA for use in patients with R/R LBCL after ≥2 prior lines of therapy. Here, we present updated data with an extended follow-up of over 3 years, a landmark analysis assessing outcomes of patients in CR, and exploratory biomarker analyses after end of treatment (EOT) evaluating the risk and benefit of fixed-duration treatment. Methods: Patients with LBCL and ≥2 prior therapies received obinutuzumab pretreatment (1000mg) on Day (D)1 of Cycle (C)1. Intravenous glofitamab was then given as step-up doses during C1 (2.5mg on D8; 10mg on D15), followed by the target dose (30mg) on D1 of C2-12 (21-day cycles). The primary endpoint was independent review committee (IRC)-assessed CR rate using Lugano criteria (Cheson, et al. J Clin Oncol 2014). Progression-free survival (PFS) and overall survival (OS) post-hoc analyses were performed in responders (landmark for CR at EOT). A modified AVENIO circulating tumor (ct)DNA analysis workflow (Roche; Research Use Only) was used for next-generation sequencing based on personalized cancer profiling; ctDNA was quantified as mutant molecules per milliliter of plasma (MMPM). CD19-positive B-cell count was measured centrally with the T, B, and natural killer cell (TBNK) assay. Results: As of May 17, 2024, 155 patients were enrolled; 154 patients had received ≥1 dose of study treatment. Baseline characteristics have been previously published (Dickinson, et al. N Engl J Med 2022). Median number of prior therapies was 3 (range: 2-7); 33% had received prior chimeric antigen receptor T-cells and 84% were refractory to their most recent regimen. Median time on study was 41.0 months (range: 0-52), with all patients with ongoing remission being treatment-free for ≥2 years following EOT. The IRC-assessed CR rate was 40% and overall response rate was 52%. After a median follow-up of 37.7 months (range: 0-51) in patients with a CR, median duration of CR was 29.8 months (95% CI: 22.0-not estimable [NE]). In patients with a CR at EOT, the PFS and OS rates 2 years after EOT were 57% and 77%, respectively. The incidence of adverse events (AEs) and serious AEs was stable compared with earlier analyses; two new Grade ≥3 AEs (neutropenia [Grade 3] and adenocarcinoma pancreas [Grade 4]) were reported. No new cytokine release syndrome events, infections, other cytopenia, or fatal AEs were reported since the previous analysis. Baseline ctDNA levels were previously shown to be prognostic in patients treated with glofitamab monotherapy. Patients with a CR at EOT and evaluable for ctDNA at baseline (27/45; 60%) showed a rapid and sustained decrease of ctDNA levels on treatment, maintained 12 months after EOT in patients with ongoing remission (baseline [n=27]: median MMPM 37.48 [range 3.13-23544.37]; C3 [n=27]: median MMPM 0.55 [range 0.00-471.18]; EOT [n=27]: median MMPM 0.29 [range 0.00-49.59]; 12 months follow-up [n=18]: median MMPM 0.04 [range 0.00-95.08]. B-cell depletion occurred in all patients during treatment; recovery of B cells and immunoglobulins was observed starting around 18 months after glofitamab treatment in patients with a sustained response after EOT. Conclusions: With this extended follow-up of over 3 years, durable responses continued to be observed with fixed-duration glofitamab in patients with R/R LBCL. The safety profile remains manageable and consistent with previous analyses. ctDNA kinetics showed that molecular response to glofitamab was rapid and sustained after EOT. Evidence of B cell and immunoglobulin recovery after EOT was observed in patients in remission. These data support the potential for long-lasting remissions and a beneficial effect on immune system recovery in patients with R/R LBCL treated with fixed-duration glofitamab.