Genmab Reports Positive Phase 3 Results for Fixed-Duration Epcoritamab Combination in Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Genmab A/S has announced positive topline results from its pivotal Phase 3 EPCORE DLBCL-4 clinical trial, demonstrating that a fixed-duration treatment regimen combining epcoritamab, a subcutaneously administered T-cell engaging bispecific antibody, with lenalidomide significantly improved outcomes for adults with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). The study successfully met its primary endpoint, showing a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when compared with the current standard-of-care regimen consisting of rituximab, gemcitabine, and oxaliplatin (R-GemOx).
The results represent another important milestone in the clinical development of epcoritamab and further strengthen evidence supporting its potential use across multiple treatment settings for patients with aggressive B-cell malignancies. Genmab indicated that the findings reinforce the growing role of epcoritamab-based combination therapies and support ongoing discussions with global regulatory authorities regarding future regulatory submissions.
Addressing an Unmet Need in Relapsed or Refractory DLBCL
Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma and is characterized by rapidly growing cancerous B lymphocytes. Although many patients respond to initial therapy, a substantial proportion eventually experience disease relapse or become refractory to treatment.
Patients whose disease returns after first-line therapy often face limited treatment options, particularly if they are not candidates for stem cell transplantation or have already received multiple lines of therapy. Outcomes generally become less favorable with each subsequent relapse, highlighting the continued need for innovative treatment approaches capable of delivering durable disease control.
The EPCORE DLBCL-4 study was designed to evaluate whether combining epcoritamab with lenalidomide could improve outcomes compared with an established chemotherapy-based regimen in patients who had received at least one previous line of treatment.
Phase 3 Trial Meets Primary Endpoint
According to Genmab, the Phase 3 trial achieved its primary objective by demonstrating a highly significant improvement in progression-free survival.
The study compared:
- Fixed-duration epcoritamab plus lenalidomide
- Standard-of-care R-GemOx (rituximab, gemcitabine, and oxaliplatin)
Among adult patients with relapsed or refractory DLBCL, treatment with the epcoritamab combination substantially reduced the likelihood of disease progression or death.
Using censoring rules applied within the United States, investigators observed a:
- 60% reduction in the risk of disease progression or death
- Hazard ratio (HR): 0.40
- 95% Confidence Interval: 0.30–0.55
- P-value: <0.0001
Using censoring rules applied outside the United States, the study demonstrated:
- 56% reduction in the risk of progression or death
- Hazard ratio (HR): 0.44
- 95% Confidence Interval: 0.33–0.60
- P-value: <0.0001
These findings indicate that patients receiving the epcoritamab combination experienced substantially longer periods without disease progression compared with those receiving the chemotherapy-based standard of care.
Clinically Meaningful Improvement
Beyond achieving statistical significance, the improvement in progression-free survival was considered clinically meaningful.
Progression-free survival is one of the most important efficacy endpoints in oncology clinical trials because it measures the length of time during which a patient’s disease remains controlled without worsening.
Reducing the risk of progression by more than half suggests that the combination therapy may offer patients longer-lasting disease control while potentially delaying the need for subsequent treatments.
The strong hazard ratios reported in the study also demonstrate consistency in treatment benefit across different regulatory methodologies used internationally.
Fixed-Duration Treatment Strategy
One notable aspect of the EPCORE DLBCL-4 study is the evaluation of a fixed-duration treatment regimen.
Unlike therapies that require continuous administration until disease progression, fixed-duration approaches aim to provide effective disease control within a defined treatment period.
This strategy may offer several potential advantages, including:
- Reduced long-term treatment burden
- Fewer ongoing clinic visits
- Improved convenience for patients
- Lower cumulative exposure to therapy
If approved, a fixed-duration regimen combining epcoritamab and lenalidomide could provide an important new option for patients seeking effective treatment without indefinite therapy.
Epcoritamab: A T-Cell Engaging Bispecific Antibody
Epcoritamab is an investigational T-cell engaging bispecific antibody administered through subcutaneous injection.
The therapy is designed to simultaneously bind:
- CD3 receptors on T cells
- CD20 proteins expressed on malignant B cells
By bringing immune T cells into close proximity with cancerous B cells, epcoritamab helps activate the body’s immune system to recognize and destroy lymphoma cells.
This mechanism differs from conventional chemotherapy by harnessing the patient’s immune response rather than relying solely on direct cytotoxic activity.
Bispecific antibodies have emerged as one of the fastest-growing areas of immuno-oncology and continue to demonstrate promising activity across several hematologic malignancies.
Combination with Lenalidomide
The study evaluated epcoritamab in combination with lenalidomide, an immunomodulatory agent that has demonstrated activity in several hematologic cancers.
Lenalidomide enhances immune system function while exerting direct anti-tumor effects through multiple biological pathways.
Combining immunomodulatory therapy with a T-cell engaging bispecific antibody may produce complementary mechanisms of action capable of improving anti-cancer activity.
The positive results from EPCORE DLBCL-4 provide further support for this combination strategy in relapsed or refractory large B-cell lymphoma.
Safety Findings
Genmab reported that the safety profile observed in the study was consistent with the previously established safety characteristics of both individual agents.
No unexpected safety signals were identified during the trial.
Specifically, investigators noted that treatment with epcoritamab plus lenalidomide demonstrated a safety profile aligned with prior experience using:
- Epcoritamab alone
- Lenalidomide alone
Maintaining a predictable safety profile is an important consideration when evaluating combination therapies, particularly in patients who have already received prior treatments for aggressive lymphoma.
Building Evidence Across Multiple Treatment Settings
Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab, said the positive Phase 3 findings add to an expanding body of evidence supporting epcoritamab-based treatment combinations across multiple stages of therapy for patients with relapsed or refractory large B-cell lymphoma.
He noted that the growing clinical program continues to demonstrate the versatility of epcoritamab, including its use as part of fixed-duration treatment strategies.
According to van de Winkel, each successful clinical study strengthens the company’s long-term vision of establishing epcoritamab as a foundational therapy across a broad range of B-cell malignancies.
He added that Genmab looks forward to working closely with regulatory authorities as development of the program continues.
Next Steps
Following the positive topline results, Genmab announced that it and its development partner AbbVie will engage with regulatory agencies worldwide regarding potential regulatory submissions.
The companies also plan to submit the full clinical data for presentation at an upcoming scientific or medical conference, where investigators are expected to provide more detailed analyses of efficacy, safety, and additional study outcomes.
These future presentations will offer clinicians and researchers a more comprehensive understanding of the treatment’s clinical performance and its potential role in managing relapsed or refractory DLBCL.
The positive Phase 3 results from the EPCORE DLBCL-4 trial represent an important advancement in the development of epcoritamab for relapsed or refractory diffuse large B-cell lymphoma. By demonstrating a statistically significant and clinically meaningful improvement in progression-free survival compared with the standard R-GemOx regimen, the study highlights the potential of fixed-duration epcoritamab plus lenalidomide to improve outcomes for patients who have already received prior therapy.
With a safety profile consistent with previous clinical experience and plans underway for regulatory discussions and scientific presentations, the findings further strengthen the growing evidence supporting epcoritamab as a versatile immunotherapy platform across B-cell malignancies. If future regulatory reviews are successful, the combination could become an important new treatment option for patients with relapsed or refractory DLBCL who continue to face significant unmet medical needs.
About the EPCORE® DLBCL-4 Trial
EPCORE DLBCL-4 (NCT06508658) is a global Phase 3 open label, multi-center, randomized trial to evaluate the efficacy of epcoritamab (GEN3013, DuoBody®-CD3xCD20) in combination with lenalidomide compared to chemoimmunotherapy, rituximab plus gemcitabine plus oxaliplatin (R-GemOx), in adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), high-grade B-Cell lymphoma (HGBL) with MYC and B-cell /lymphoma 2 (BCL2) and/or BCL6 rearrangements, follicular lymphoma grade 3B (FL3B), T-cell/histiocyte-rich large B-Cell lymphoma (TCHR LBLC), and Epstein-Barr Virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL).
Patients in the trial were previously treated with at least one line of systemic antineoplastic therapy including anti-CD20 mAb-containing combination chemotherapy, and failed or relapsed after, or were not a candidate for autologous stem cell transplantation (ASCT) and ineligible for or unable to receive CAR-T since DLBCL diagnosis. The trial started on August 13, 2024, and is ongoing.
More information on this trial can be found at https://clinicaltrials.gov/study/NCT06508658 (NCT: NCT06508658).
About Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) DLBCL is the most common type of non-Hodgkin lymphoma (NHL) worldwide, accounting for approximately 25-30 percent of all NHL cases.i,ii In the U.S., there are approximately 25,000 new cases of DLBCL diagnosed each year.iii DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system, occurs more commonly in the elderly and is slightly more prevalent in men.iv,v
DLBCL is a fast-growing type of NHL, a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. For many people living with DLBCL, their cancer either relapses, which means it may return after treatment, or becomes refractory, meaning it does not respond to treatment. Although new therapies have become available, treatment management can remain a challenge.iv,vi
About Epcoritamab
Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody® technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.vii
Epcoritamab (approved under the brand name EPKINLY® in the U.S. and Japan, and TEPKINLY® in the EU) has received regulatory approval in certain lymphoma indications in more than 65 territories. Where approved, epcoritamab is a readily accessible therapy. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for R/R FL indication and additional approvals for the R/R DLBCL indication.
Genmab and AbbVie continue to evaluate epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes several ongoing Phase 3, open-label, randomized trials, among them a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT05578976) and a trial evaluating epcoritamab in combination with lenalidomide and rituximab (R2) compared to chemoimmunotherapy in patients with previously untreated FL (NCT06191744). The safety and efficacy of epcoritamab have not been established for these investigational uses. Please visit www.clinicaltrials.gov for more information.
Please see local country prescribing information for all labeled indication and safety information.
About Genmab
Genmab is an international biotechnology company dedicated to improving the lives of people with cancer and other serious diseases through innovative antibody medicines. For over 25 years, its passionate, innovative and collaborative team has advanced a broad range of antibody-based therapeutic formats, including bispecific antibodies, antibody–drug conjugates (ADCs), immune-modulating antibodies and other next-generation modalities. Genmab’s science powers eight approved antibody medicines, and the company is advancing a strong late-stage clinical pipeline, including wholly owned programs, with the goal of delivering transformative medicines to patients.
