Fixed-Duration Epcoritamab Shows Strong Responses in Older, Chemo-Ineligible Patients With LBCL

A new analysis from the phase 2 EPCORE DLBCL-3 trial (NCT05660967) suggests that fixed-duration epcoritamab (Epkinly; Genmab and AbbVie) monotherapy may offer a highly effective, chemotherapy-free treatment option for elderly patients with newly diagnosed large B-cell lymphoma (LBCL) who cannot tolerate standard anthracycline-based regimens.

The findings demonstrate rapid, deep, and durable responses, notably high rates of complete remission and early minimal residual disease (MRD) negativity, in a population with few viable frontline therapies and historically poor outcomes.

“These findings, together with those from other trials (EPCORE NHL-2; NCT04663347), show that epcor, as monotherapy or combined with other treatment, can be a favorable option for pts with 1L DLBCL across a broad range of ages and fitness levels,” wrote researchers of the study, detailing their findings in Blood.

Traditional first-line treatment for LBCL relies on full-dose R-CHOP chemotherapy, but many older LBCL patients cannot tolerate the treatment due to comorbidities, and reduced-intensity options like R-mini-CHOP offer only limited effectiveness. In recent years, bispecific antibodies have shown promise in relapsed or refractory LBCL, but evidence in the frontline setting has been limited. The EPCORE DLBCL-3 trial is the first to rigorously test frontline epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, in this high-risk, chemotherapy-ineligible population.

The trial enrolled 66 patients across 2 stages, with stage 2 focusing exclusively on epcoritamab monotherapy following encouraging results from stage 1. Patients received step-up dosing in cycle 1, followed by weekly injections during cycles 1 through 3 and monthly dosing through cycle 12, constituting a fixed 1-year treatment course.

With a median follow-up of 14.9 months, results showed robust antitumor activity. Among 53 response-evaluable patients, the overall response rate was 70%, and more than half (58%) of patients achieved complete remission (CR). Responses occurred after a median of 1.5 months, and time to CR occurred after a median of 2.2 months. Notably, some patients who initially showed partial response or stable disease converted to CR at later assessments, emphasizing the depth of therapeutic effect with epcoritamab.

The researchers also observed strong durability signals, with median duration of response and median duration of CR not reached at the time of reporting. At 12 months, an estimated 72% of all responses and 79% of complete responses remained ongoing. In the full trial population, median progression-free survival (PFS) was 13 months, and median overall survival had not yet been reached, with an estimated 65% of patients alive at one year.

The researchers highlighted the real-world complexity and high unmet need of the patients included in their study. All patients included in the trial had at least 1 significant comorbidity, and many had multiple: vascular disorders were present in 80%, renal impairment in 64%, and cardiac disorders in 41%. Nearly two-thirds had stage IV disease, and one-third had bulky tumors measuring 7 cm or more.

One of the most compelling findings was the high rate of minimal residual disease (MRD) negativity. Among 26 MRD-evaluable patients, 88% achieved undetectable circulating tumor DNA at any point during treatment. MRD negativity occurred early—often by cycle 3—and was sustained in many patients through cycle 12. MRD-negative patients demonstrated longer PFS, reinforcing MRD’s value as a potential surrogate marker of long-term benefit.

Safety outcomes were consistent with previous epcoritamab studies² and generally manageable. Ninety-four percent of patients experienced treatment-emergent side effects, most commonly cytokine release syndrome (CRS) (70%), diarrhea (23%), and fatigue (21%).¹ CRS was predominantly low-grade—38% were grade 1 and 27% were grade 2—and nearly all CRS events occurred in cycle 1 and resolved. Immune effector cell-associated neurotoxicity syndrome occurred in 18% of patients, mostly grade 1 or 2, with 10 of 12 cases resolving by data cutoff. Infections were observed in 59% of patients, but only 18% were grade 3 or higher. There were no cases of febrile neutropenia or clinical tumor lysis syndrome.

Still, the vulnerable nature of the study population contributed to treatment discontinuations. About 48% of patients discontinued therapy, most commonly due to disease progression or side effects. Two treatment-related deaths occurred: 1 from pneumonia and 1 from sepsis during early treatment escalation.

References

1. Vitolo U, Duell J, Burgues JMB, et al. Fixed-duration epcoritamab monotherapy induces high response and MRD-negativity rates in elderly patients with newly diagnosed large B-cell lymphoma (LBCL) and comorbidities: Results from EPCORE DLBCL-3. Blood. 2025.146(S1):63. doi:10.1182/blood-2025-63

2. Epkinly. Genmab; 2025. Acessed December 24, 2025. https://www.genmab-pi.com/prescribing-information/epkinly-pi.pdf