Epcoritamab’s Emerging Role: Redefining DLBCL Treatment for High-Risk and Older Patients
An 82% overall survival rate at two years – a figure once considered unattainable for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) deemed too frail for standard chemotherapy – is now within reach, thanks to promising data unveiled at the American Society of Hematology (ASH) 2025 meeting. The EPCORE NHL-2 trial is demonstrating that combining the immunotherapy epcoritamab with modified chemotherapy regimens isn’t just extending lifespans, it’s achieving remarkably high remission rates even in populations historically facing a poor prognosis.
The Challenge of Treating High-Risk DLBCL
Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, but its aggressiveness and variability present significant treatment hurdles. Many patients, particularly those over 75 or with significant comorbidities, are ineligible for the standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy due to its intensity. This leaves clinicians searching for effective, less toxic alternatives. The International Prognostic Index (IPI) is often used to assess risk, and patients with higher IPI scores (3-5) generally have worse outcomes.
EPCORE NHL-2: A Two-Pronged Approach to Improved Outcomes
The EPCORE NHL-2 trial explored two distinct strategies for integrating epcoritamab into DLBCL treatment. The first arm focused on older or frail patients ineligible for full-dose R-CHOP, utilizing a reduced-intensity regimen – R-mini-CHOP – alongside epcoritamab. This combination yielded impressive results: an 89% overall response rate (ORR) and a complete response (CR) rate of 86%. Critically, 95% of evaluable patients achieved minimal residual disease (MRD) negativity, a strong predictor of long-term remission, using the AVENIO Oncology ctDNA assay.
The Power of MRD Negativity
MRD negativity, meaning no detectable cancer cells remaining after treatment, is increasingly recognized as a crucial endpoint in lymphoma trials. The EPCORE NHL-2 data showed that achieving MRD negativity early in treatment (cycle 3) was strongly associated with sustained remission. This highlights the potential of ctDNA monitoring to personalize treatment and identify patients who may benefit from further intervention.
The second arm of the trial investigated epcoritamab in combination with standard R-CHOP, followed by epcoritamab monotherapy. This approach demonstrated even higher ORR (98%) and CR rates (85%) in patients with higher IPI scores (3-5), with durable responses observed over a median follow-up of nearly four years. The sustained remission rates – 67% of responses and 75% of CRs ongoing at 33 months – are particularly encouraging.
Safety Considerations and Manageable Side Effects
While epcoritamab is generally well-tolerated, the trials did report grade 3 or greater infections in up to 29% of patients. However, these infections were primarily observed in the first six months of treatment, and no new grade 5 events (treatment-related death) were reported. Careful monitoring and proactive management of infections are essential when using epcoritamab-based regimens.
Looking Ahead: The Future of DLBCL Treatment
The EPCORE NHL-2 trial data strongly suggest that epcoritamab is poised to become a cornerstone of DLBCL treatment, particularly for high-risk and older patients. The success of both treatment strategies – epcoritamab plus R-mini-CHOP and epcoritamab plus R-CHOP followed by monotherapy – offers clinicians flexibility in tailoring treatment to individual patient needs. The increasing emphasis on MRD negativity as a treatment goal, coupled with the availability of sensitive ctDNA assays, will likely drive further refinement of DLBCL treatment algorithms.
The potential for combining epcoritamab with other novel agents, such as bispecific antibodies or CAR T-cell therapy, is also an exciting area of ongoing research. As we move towards more personalized and precise approaches to lymphoma treatment, epcoritamab is leading the charge, offering renewed hope for patients who previously had limited options. The shift towards fixed-duration therapies, as demonstrated in the EPCORE NHL-2 trial, also represents a significant improvement over traditional, prolonged chemotherapy regimens, reducing treatment burden and improving quality of life.
What are your thoughts on the role of MRD negativity in guiding DLBCL treatment decisions? Share your perspective in the comments below!
