Odronextamab Monotherapy in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma: Primary Efficacy and Safety Analysis in Phase 2 ELM-2 Trial

Immunology Life Sciences Oncology Hematology Medicine
Diffuse Large B Cell Lymphoma Relapsed/Refractory Odronextamab ELM-2 Trial Safety Efficacy Cytokine Release Syndrome

Academic Background

Diffuse Large B Cell Lymphoma (DLBCL) is an aggressive form of B-cell non-Hodgkin lymphoma (B-NHL), accounting for approximately 30% of all non-Hodgkin lymphomas. Although first-line immunochemotherapy (e.g., R-CHOP regimen) has shown efficacy in DLBCL patients, about 30% of patients relapse or become refractory (relapsed/refractory, R/R) after first-line treatment. For these patients, particularly those with primary refractory disease, the median overall survival (OS) is only 6-7 months, indicating a poor prognosis. Therefore, the development of effective treatment options for R/R DLBCL has become an urgent clinical need.

In recent years, T-cell engaging therapies, such as chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies, have shown significant potential in the treatment of R/R DLBCL. While CAR-T therapy has demonstrated remarkable efficacy in some patients, its application is limited by factors such as complex manufacturing processes, high costs, and severe side effects (e.g., cytokine release syndrome, CRS). As a result, bispecific antibodies, as an “off-the-shelf” treatment option, have gradually become an important supplement to R/R DLBCL therapy.

Odronextamab is an Fc-silenced humanized CD20×CD3 bispecific antibody that simultaneously binds CD20 on malignant B cells and CD3 on cytotoxic T cells, thereby inducing T-cell-mediated B-cell killing. This study aims to evaluate the long-term efficacy and safety of Odronextamab in R/R DLBCL patients, particularly in those who have failed CAR-T therapy.

Source of the Paper

This paper was authored by a team of researchers from multiple international institutions, with the primary authors including Won Seog Kim (Sungkyunkwan University School of Medicine, Samsung Medical Center) and Tae Min Kim (Seoul National University Hospital), among others. The study was published in March 2025 in the journal Nature Cancer, titled “Odronextamab monotherapy in patients with relapsed/refractory diffuse large b cell lymphoma: primary efficacy and safety analysis in phase 2 elm-2 trial.”

Study Process and Results

Study Design

This study is a multi-cohort, open-label phase II clinical trial (ELM-2) designed to evaluate the efficacy and safety of Odronextamab in R/R B-NHL patients. This paper reports the long-term follow-up results of the DLBCL cohort. The study enrolled 127 R/R DLBCL patients, all of whom had received at least two lines of systemic therapy, including anti-CD20 antibodies and alkylating agents.

Treatment Regimen

Patients received intravenous Odronextamab in 21-day cycles until disease progression or intolerable toxicity. To mitigate the risk of CRS, a step-up dosing regimen was employed. The specific regimens included: 1. Initial Regimen: 1 mg (0.5 mg on day 1, 0.5 mg on day 2) → 20 mg (10 mg on day 8, 10 mg on day 9) → 160 mg (on day 15). 2. Optimized Regimen: 0.7 mg (0.2 mg on day 1, 0.5 mg on day 2) → 4 mg (on days 8 and 9) → 20 mg (on days 15 and 16) → 160 mg (on day 22).

Primary and Secondary Endpoints

The primary endpoint was the objective response rate (ORR), and the secondary endpoints included the complete response rate (CR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

Study Results

  1. Efficacy Analysis:

    • ORR and CR Rate: At a median follow-up of 29.9 months, the ORR was 52.0% (66⁄127), and the CR rate was 31.5% (40⁄127).
    • Duration of Response: The median DoR was 10.2 months, and the median DoR for CR patients was 17.9 months.
    • PFS and OS: The median PFS was 4.4 months, and the median OS was 9.2 months. CR patients had significantly better PFS and OS than partial response (PR) patients (PFS: 20.4 months vs. 5.8 months; OS: not reached vs. 17.0 months).

  2. Biomarker Analysis:

    • At cycle 4 day 15 (C4D15), 20⁄63 patients achieved minimal residual disease (MRD) negativity (MRD-). MRD- patients had significantly better PFS than MRD+ patients (HR=0.27).

  3. Safety Analysis:

    • Treatment-Emergent Adverse Events (TEAEs): TEAEs were reported in 99.2% of patients, with the most common being CRS (55.1%), pyrexia (43.3%), and anemia (38.6%). Grade ≥3 TEAEs occurred in 84.3% of patients, with the most common being neutropenia (26.0%) and anemia (22.8%).
    • Infections: Infections were reported in 64.6% of patients, with COVID-19 infections accounting for 18.1%.
    • CRS Management: Tocilizumab was used in 25% of patients, and systemic steroids were used in 21.7% of patients. No patients required mechanical ventilation or intensive care unit admission due to CRS.

Conclusions and Significance

This study demonstrates that Odronextamab shows significant efficacy in highly refractory R/R DLBCL patients, particularly in those who have failed CAR-T therapy. Its ORR and CR rates are comparable to those of existing bispecific antibodies (e.g., Glofitamab and Epcoritamab), and its safety profile is manageable. Furthermore, the association between MRD clearance and improved PFS suggests that early MRD assessment may have prognostic value.

Highlights of the Study

  1. Innovative Treatment Regimen: Odronextamab effectively reduces the incidence of CRS through step-up dosing, particularly in the optimized regimen, where the rate of grade ≥3 CRS is significantly lower.
  2. Broad Applicability: Odronextamab demonstrates consistent efficacy across multiple high-risk subgroups, including elderly patients, those with multiple treatment failures, and double-refractory patients.
  3. Prognostic Value of MRD: The association between early MRD clearance and improved PFS provides important insights for optimizing future treatment strategies.

Other Valuable Information

This study also explores the potential of Odronextamab in outpatient settings, which could improve treatment accessibility, particularly in resource-limited regions. Additionally, the research team plans to conduct phase III clinical trials to further evaluate the application of Odronextamab in earlier lines of therapy.

As a novel bispecific antibody, Odronextamab offers an effective treatment option for R/R DLBCL patients, particularly those who have failed CAR-T therapy. Its significant efficacy and manageable safety profile make it a promising addition to the future treatment landscape for DLBCL.