Real-world outcomes of glofitamab monotherapy in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma: a multicenter Korean cohort

Technical Summary: Real-world Outcomes of Glofitamab Monotherapy in Heavily Pretreated RR-DLBCL

Problem Statement
Glofitamab, a CD20×CD3 bispecific antibody, has demonstrated efficacy in the pivotal NP30179 trial for relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). However, real-world data regarding its monotherapy use remains limited, particularly within Asian cohorts and specifically for patients who have failed prior chimeric antigen receptor T-cell (CAR-T) therapy. While CAR-T is the standard of care, more than half of recipients eventually progress, and no established standard of care exists for this population. Furthermore, access to CAR-T is often constrained by manufacturing delays and cost, necessitating effective "off-the-shelf" alternatives. There is a critical need to evaluate the efficacy, safety, and prognostic factors of glofitamab in a heavily pretreated, real-world setting to guide treatment sequencing and patient selection.

Methodology
This multicenter retrospective study analyzed data from 46 patients with RR-DLBCL treated with glofitamab monotherapy across four centers in Korea (Samsung Medical Center, Korea University Anam Hospital, Yeouido St. Mary's Hospital, and Seoul National University Hospital). The study period spanned from the drug's regulatory approval in Korea (December 2023) through December 2025, with a clinical follow-up cutoff in March 2026.

• Cohorts: The analysis utilized a "full cohort" (n=46) for response and safety endpoints and a "primary cohort" (n=41) for survival analyses. The primary cohort excluded five patients treated with a bridging intent to subsequent cellular therapy or transplantation to avoid confounding survival data.
• Patient Profile: The population was heavily pretreated, with a median of 3 prior lines of therapy (range 1–11). Notably, 58.7% (27/46) had failed prior CAR-T therapy.
• Treatment Protocol: Patients received glofitamab according to the approved step-up dosing schedule (2.5 mg on Cycle 1 Day 8, 10 mg on Cycle 1 Day 15, followed by 30 mg every 21 days). Obinutuzumab (1000 mg) was administered on Day 1 of Cycle 1 for B-cell depletion, and corticosteroid premedication was mandatory.
• Endpoints: Primary endpoints included Objective Response Rate (ORR), Complete Response (CR) rate, Progression-Free Survival (PFS), Overall Survival (OS), and Duration of Response (DOR). Safety endpoints included Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), graded by ASTCT criteria.
• Statistical Analysis: Survival curves were generated using Kaplan-Meier estimates. Cox proportional hazards regression (univariable and multivariable) was used to identify factors associated with survival, specifically examining the interval between the last prior therapy and glofitamab initiation (<1 month, 1–3 months, ≥3 months).

Key Contributions

1. Real-World Validation in High-Risk Asian Cohort: This study provides the first comprehensive real-world data on glofitamab monotherapy in a Korean population, confirming its activity in a setting where 59% of patients had previously failed CAR-T therapy.
2. Identification of a Prognostic Variable: The study identifies the "pre-glofitamab treatment interval" (time from last therapy to glofitamab initiation) as a critical, readily assessable clinical variable. It demonstrates that patients progressing within one month of their last therapy derive significantly less benefit.
3. Safety Profile in Post-CAR-T Patients: The study confirms that prior CAR-T exposure does not exacerbate the safety profile of glofitamab, specifically regarding CRS and ICANS, supporting its use as a subsequent-line therapy for CAR-T failures.
4. Bridging Potential: The data suggests a role for glofitamab as a bridging strategy to consolidate therapy (e.g., allogeneic hematopoietic cell transplantation) in patients who achieve a response, even in the post-CAR-T setting.

Results

• Efficacy: In the full cohort (n=46), the ORR was 39.1% (18/46), with a CR rate of 32.6% (15/46). In the primary cohort (n=41), the median PFS was 2.6 months and median OS was 5.9 months.
• Durability: Responses were durable among responders. The median DOR was not reached. The PFS curve plateaued at approximately 21% beyond 6 months, indicating a subset of patients achieving long-term disease control.
• Impact of Prior CAR-T: There was no significant difference in survival outcomes between patients with prior CAR-T exposure and those without (Median OS: 6.1 vs. 2.9 months; p=0.329).
• Impact of Treatment Interval: A longer interval between the last prior therapy and glofitamab initiation was strongly associated with improved outcomes.
  • <1 month: ORR 15.4%, Median PFS 1.0 month.
  • 1–3 months: ORR 43.8%, Median PFS 2.9 months.
  • ≥3 months: ORR 50.0%, Median PFS 2.9 months (trend toward longer OS).
  • Multivariable analysis confirmed the interval as an independent predictor of PFS (Adjusted HR 0.51 per category increase, p=0.018).
• Safety: CRS occurred in 26.1% of patients, all of which were Grade 1 or 2. No Grade ≥3 CRS, no ICANS, and no treatment-related deaths were observed. Infection rates were comparable between prior CAR-T and CAR-T-naïve groups.

Significance and Claims
The authors claim that glofitamab monotherapy offers "meaningful activity and manageable safety" for heavily pretreated RR-DLBCL patients, including those who have failed CAR-T therapy. The study highlights that while the overall median survival is limited by the refractory nature of the population, a significant subset of patients achieves durable remissions.

A central claim is the clinical utility of the pre-glofitamab treatment interval. The authors assert that patients progressing within one month of their last therapy represent a high-risk subgroup with limited benefit from standard glofitamab monotherapy. This observation warrants prospective evaluation to determine if alternative strategies (e.g., combination regimens or accelerated dosing) are necessary for this specific group.

The paper concludes that glofitamab is a viable option for patients with exhausted treatment options and that the treatment-free interval serves as a practical tool for risk stratification and treatment sequencing. The authors emphasize that their findings are modest due to the retrospective nature, small sample size, and lack of central review, calling for prospective validation to define the optimal role of treatment-free intervals in optimizing bispecific antibody therapy.