Clinical Summary:

• Design/Population: The global, phase 3 EPCORE DLBCL-1 trial randomized 483 patients with CD20-positive relapsed or refractory large B-cell lymphoma who were ineligible for autologous stem cell transplantation or had relapsed following transplantation to receive epcoritamab monotherapy or investigator’s choice chemoimmunotherapy. 
• Key Outcomes: Epcoritamab significantly improved progression-free survival compared with chemoimmunotherapy. Complete response rates were higher with epcoritamab, median duration of response was substantially longer, and time to next treatment improved. Overall survival was not significantly different in the primary analysis, although adjusted analyses accounting for COVID-19–related deaths and subsequent therapies favored epcoritamab. 
• Clinical Relevance: These findings establish epcoritamab as the first CD3×CD20 bispecific antibody monotherapy to demonstrate a statistically significant progression-free survival advantage over standard chemoimmunotherapy in relapsed or refractory large B-cell lymphoma.

Christopher Fox, MD, PhD, University of Nottingham, Nottingham, United Kingdom, discusses results from the phase 3 EPCORE DLBCL-1 trial evaluating epcoritamab monotherapy versus investigator’s choice chemoimmunotherapy in patients with relapsed or refractory large B-cell lymphoma. The study enrolled a heavily pretreated population, including patients with transformed follicular lymphoma, double-hit lymphoma, prior stem cell transplantation, and prior CAR T-cell therapy.

Epcoritamab significantly prolonged progression-free survival and produced deeper, more durable remissions than chemoimmunotherapy, with nearly 40% of patients achieving complete responses and almost 60% of complete responders remaining in remission at 3 years. Although the overall survival endpoint was not met, outcomes were likely influenced by COVID-19–related mortality and greater use of effective subsequent therapies—including CAR T-cell therapy, bispecific antibodies, and stem cell transplantation—in the control arm, while the safety profile remained consistent with prior experience.

Dr Fox presented these results at the European Hematological Association (EHA) Annual Meeting in Stockholm, Sweden. 

Transcript: 

Hello, my name is Chris Fox, I'm a professor of hematology in Nottingham in the UK. At the European Hematology Association meeting, on June 12, I presented the first data from the EPCORE DLBCL-1 study, and I'd like to summarize some of the key findings.

EPCORE DLBCL-1 is the largest randomized study conducted to date in relapsed or refractory DLBCL. The study focused on patients who were either ineligible for autologous stem cell transplant or had relapsed following autologous stem cell transplant. This was a large global phase 3 study conducted across 166 sites in approximately 24 countries.

Patients were randomized to receive either epcoritamab monotherapy, given according to the standard dosing schedule, and continued until progression, or investigator’s choice of chemoimmunotherapy. In the chemoimmunotherapy arm, nearly three-quarters of patients received R-GemOx, which has become a commonly used comparator regimen in recent randomized studies. Most of the remaining patients received bendamustine plus rituximab. The eligibility criteria were broad and included patients with transformed follicular lymphoma and double-hit lymphoma.

This was also a heavily pretreated population. Approximately one-quarter of patients had received only one prior line of therapy and entered the study in the second-line setting, but about three-quarters had received three or more prior lines of therapy. Many patients were primary refractory or refractory to multiple previous treatments. The median age was 72 years. The study had dual primary end points: progression-free survival and overall survival. The study was powered independently for each end point, meaning that only 1 of the 2 needed to be positive for the study to be considered successful.

The headline result is that progression-free survival was both statistically and clinically superior with epcoritamab. There was a 26% reduction in the risk of progression or death, corresponding to a hazard ratio of 0.74. We now have relatively mature follow-up, with just over 3 and a half years of observation. When we examine the Kaplan-Meier curves, we see progressive separation over time, such that by three years nearly all patients in the chemoimmunotherapy arm had experienced progression or death.

The progression-free survival benefit translated into improvements in duration of response and duration of complete response. Importantly, nearly 40% of patients achieved a complete response with epcoritamab, and of those patients, just under 60% remained in complete response at the 3-year mark. 

We also presented data from the second-line subgroup. Although this was a smaller subset of patients, we again observed a clear progression-free survival benefit, raising the possibility that single-agent epcoritamab could be particularly useful in this setting. 

We also reviewed the safety data. It's important to recognize that safety reporting differs between a treatment-until-progression strategy and a shorter-duration chemoimmunotherapy approach, meaning that more safety information accumulates in the epcoritamab arm. There were more serious treatment-related adverse events reported with epcoritamab, largely driven by cytokine release syndrome. Most CRS events were low grade, with approximately 17% grade 2 and 3% grade 3 events.

We also observed more fatal adverse events in the epcoritamab arm. Again, this needs to be interpreted in the context of longer exposure and longer reporting periods. More than half of these fatal events were related to COVID-19, as study enrollment overlapped with the Omicron phase of the pandemic. The remaining fatal adverse events were primarily due to infections.

In summary, this study demonstrated a significant progression-free survival advantage for bispecific antibody monotherapy. To our knowledge, this is the first time a bispecific monotherapy has been shown to be superior to chemoimmunotherapy in a randomized phase 3 study in relapsed or refractory DLBCL. 

We did not observe an overall survival advantage favoring epcoritamab at this analysis. We believe there are two main reasons for this. First, there was early mortality, much of it related to COVID-19. Second, many more patients in the chemoimmunotherapy arm received highly effective subsequent therapies after progression, including CAR T-cell therapy, bispecific antibodies, or stem cell transplantation. Specifically, 31% of patients in the chemoimmunotherapy arm received one of these subsequent therapies compared with only 6% of patients in the epcoritamab arm. We were able to show that this difference likely influenced overall survival outcomes.

Overall, this is an important study demonstrating a clear benefit for patients treated with bispecific antibody monotherapy. I encourage you to review the full EHA presentation and to explore the broader epcoritamab development program in DLBCL. 

Source: 

Fox CP, Inchiappa L, Ferhanoglu B, et al. Results from EPCORE DLBCL-1: Randomized phase 3 study of epcoritamab (Epcor) vs investigator’s choice chemoimmunotherapy (CIT) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Presented at EHA Congress. June 11 - June 14, 2026. Stockholm, Sweden. Abstract EHA-2409.