Epcoritamab Significantly Improves PFS Vs Chemoimmunotherapy in R/R Large B-Cell Lymphoma

Epcoritamab-bysp (Epkinly) monotherapy significantly improved progression-free survival (PFS) compared with investigator's choice of chemoimmunotherapy (CIT) in patients with relapsed/refractory large B-cell lymphoma (LBCL), meeting one of the dual primary end points of the phase 3 EPCORE DLBCL-1 trial (NCT04628494).¹

The data, which were shared during the 2026 EHA Congress, showed that at a median follow-up of 38.6 months (95% CI, 33.0-38.9) in the epcoritamab arm (n = 168) and 28.2 months (95% CI, 22.1-44.2) in the CIT arm (n = 178), the median PFS by independent review committee (IRC) assessment was 3.5 months (95% CI, 2.9-4.6) with epcoritamab vs 3.0 months (95% CI, 2.9-4.1) with CIT (stratified HR, 0.74; 95% CI, 0.60-0.92; P = .0059). The Kaplan-Meier curves separated progressively over time, with landmark PFS rates of 35% vs 18% at 12 months, 30% vs 13% at 24 months, and 27% vs 8% at 36 months, respectively.

The co-primary end point of overall survival (OS) was not significantly different between the arms (stratified HR, 0.96; 95% CI, 0.77-1.20; P = .7285).

“There’s a progressive separation of the Kaplan-Meier curves, which indicates the depth and durability of the epcoritamab responses compared to [chemoimmunotherapy],” said Christopher P. Fox, PhD, MBChB(Hons), FRCP, FRCPath, during the presentation.

Fox is a clinical professor of hematology in the Faculty of Medicine and Health Sciences at the University of Nottingham and an honorary consultant hematologist and lymphoma lead at Nottingham University Hospitals NHS Trust in the United Kingdom.

Why do the EPCORE DLBCL-1 results matter for relapsed/refractory large B-cell lymphoma?

Up to 40% of patients with newly diagnosed LBCL develop relapsed or refractory disease after first-line treatment, and outcomes are particularly poor for those who are ineligible for or relapse after high-dose therapy with autologous stem cell transplantation (HDT-ASCT).²

In the international SCHOLAR-1 analysis, patients with refractory diffuse large B-cell lymphoma had an objective response rate (ORR) of 26% with a complete response (CR) rate of 7% to the next line of therapy and a median OS of 6.3 months, with 20% alive at 2 years.³ Standard CIT options for transplant-ineligible patients include rituximab (Rituxan) plus gemcitabine and oxaliplatin (R-GemOx) and bendamustine plus rituximab (BR).

“It’s clear that we need more effective, accessible treatment options that can deliver durable responses for this patient group,” Fox said.

Epcoritamab, a subcutaneously administered CD3xCD20 bispecific antibody, was approved by the FDA in May 2023 for use in adult patients with relapsed/refractory DLBCL after at least 2 prior lines of systemic therapy.⁴ The decision was based on findings from the pivotal phase 1/2 EPCORE NHL-1 trial (NCT03625037), in which the agent elicited an ORR of 61% (95% CI, 53%-69%), which included a CR rate of 38% in patients with CD20-positive DLBCL who were enrolled in the expansion cohort of the trial (n = 148). At a median follow-up of 9.8 months in responders, the median duration of response (DOR) with epcoritamab was estimated to be 15.6 months (95% CI, 9.7-not reached [NR]).

“[EPCORE DLBCL-1] is the largest phase 3 study conducted to date in relapsed or refractory large B-cell lymphoma, and these are the primary results at just over 3.5 years of follow-up,” Fox said. “This was a global study—a huge effort from 166 sites over 24 countries.”

How was the EPCORE DLBCL-1 trial designed?

The global, open-label, phase 3 EPCORE DLBCL-1 trial enrolled patients with CD20-positive relapsed/refractory LBCL, which included de novo and transformed disease, double-hit/triple-hit DLBCL, grade 3B follicular lymphoma, and T-cell/histiocyte-rich LBCL. Patients had received at least 1 prior systemic line of therapy, had an ECOG performance status no higher than 2, and were not eligible for or had relapsed after HDT-ASCT.

“It's also important to note that the enrollment for this trial coincided with the Omicron phase of the COVID-19 pandemic, so two-thirds of patients were randomized during this Omicron phase,” Fox said.

A total of 483 patients were randomly assigned 1:1 to subcutaneous epcoritamab at 48 mg in 28-day cycles until disease progression or intolerable toxicity (n = 241) or investigator’s choice of CIT (n = 242), with R-GemOx selected for 174 patients and BR for 68 patients.

The dual primary end points were PFS by IRC and Lugano criteria and OS. Secondary end points included ORR, CR rate, and duration of response per IRC and Lugano criteria, time to next treatment (TTNT), and safety.

The median patient age was 72.0 years (range, 31-89) in the epcoritamab arm and 71.0 years (range, 28-88) in the CIT arm. In the epcoritamab arm, 43% of patients were between the ages of 65 years and 75 years, and 34% were aged 75 years or older; these respective rates were 38% and 32% in the CIT arm. Moreover, 49% and 14% of patients in the epcoritamab arm had an ECOG performance status of 1 or 2 vs 39% and 14% of those in the CIT arm, respectively.

“There was a higher number of patients with double-hit disease in the epcoritamab arm,” Fox said. “The treatment history is really important to look at in relapsed/refractory DLBCL studies to get a sense of how difficult [to treat] these patients may be. You'll notice that approximately three-quarters of patients were treated as third-line plus in the trial, and one-third of patients were actually treated as fourth line within this study. Over half of the patients were primary refractory, speaking to the difficult nature of this enrolled population.”

What were the response and survival outcomes with epcoritamab vs chemoimmunotherapy?

The CR rate was 38% with epcoritamab vs 26% with CIT (nominal P = .0032). The median duration of complete response (DOCR) was NR (95% CI, 32.9-NR) with epcoritamab vs 10.8 months (95% CI, 5.6-20.6) with CIT, with 59% vs 24% of complete responders maintaining CR at 36 months, respectively.

“Both duration of response and duration of complete response compare very favorably with the pivotal [EPCORE] NHL-1 data, consolidating and extending the data for epcoritamab in this setting, and you'll note nearly 60% of patients in this landmark analysis remained in CR at the 3-year time point,” Fox underscored.

“This efficacy difference translated into a significantly shorter time-to-next treatment in the CIT arm, so this equated to an approximately 40% reduction in risk of requiring a subsequent treatment for the epcoritamab patients,” Fox said. The median TTNT was 6.6 months (95% CI, 4.5-13.3) with epcoritamab vs 4.3 months (95% CI, 3.7-5.2) with CIT (stratified HR, 0.62; 95% CI, 0.50-0.78; P < .0001).

“There was significantly more CAR-T cell therapy, bispecific antibody therapy, and stem cell transplant used as a subsequent treatment in the CIT arm compared to the epcoritimab arm, and in total, this is 31% vs 6% [of patients, respectively],” Fox said. “This, of course, reflects more progressive disease events in the CIT arm and also reflects the evolving treatment landscape and increased availability of these effective subsequent therapies.”

Subsequent SCT was leveraged in 6% of those on the CIT arm vs 2% of those on the epcoritamab arm; CAR T-cell therapy was administered to 11% vs 3% of patients, and subsequent bispecific antibody therapy to 14% vs 1% of patients, respectively.

Although unadjusted OS did not differ between arms, Fox reported that the end point was confounded by COVID-19 mortality and the higher use of effective subsequent therapies in the CIT arm. In a post hoc analysis adjusting for both factors, the median OS was 16.7 months (95% CI, 10.9-26.3) with epcoritamab vs 9.5 months (95% CI, 8.7-11.7) with CIT (stratified HR, 0.76; 95% CI, 0.59-0.99). “We see a hazard ratio of 0.76, but [we] acknowledge that this is a post hoc analysis,” Fox said.

Investigators also examined the impact of subsequent bispecific antibody, CAR T-cell therapy, and SCT on OS. “In the CIT arm, if you consider patients who survive 12 months or more, almost half of those patients are already on a subsequent therapy,” Fox noted. “If thinking about patients who survived 12 months or more, only approximately 10% of patients in the epcoritamab arm have needed to have a subsequent therapy.”

Among patients with a single prior line of therapy, the median PFS with epcoritamab in this subgroup was 6.0 months (95% CI, 3.0-38.7) vs 5.6 months (95% CI, 3.0-7.9) with CIT (unstratified HR, 0.67; 95% CI, 0.44-1.04). “The Kaplan-Meiers for PFS show clear superiority of epcoritamab,” Fox said. “We acknowledge that the total numbers limit the statistical significance.”

The median OS in the respective arms was 40.2 months (95% CI, 13.8-NR) and 17.8 months (95% CI, 8.4-30.9; unstratified HR, 0.80; 95% CI, 0.51-1.25). Moreover, in this group, the CR rate was 45% with epcoritamab vs 38% with CIT (OR, 1.35; 95% CI, 0.63-2.89).

What did the safety analysis of epcoritamab show?

The mean treatment duration was 11.2 months with epcoritamab vs 2.1 months with CIT, and treatment remained ongoing in 28 patients (12%) in the epcoritamab arm. “Treatment exposure is very relevant to safety data interpretation, particularly when we're looking at treatment to progression and therapy compared to a fixed duration, and we have nearly a third of patients in the epcoritamab arm who completed or initiated more than 12 cycles of epcoritamab treatment, and treatment, in fact, is ongoing in 28 patients,” Fox said.

Grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 76% of epcoritamab-treated patients vs 79% of CIT-treated patients, and exposure-adjusted event rates favored epcoritamab (20% vs 85.7%). Serious TEAEs were more frequent with epcoritamab (69% vs 32%). TEAEs led to treatment discontinuation in 20% vs 11% of patients, respectively. Fatal TEAEs were reported in 17% of the epcoritamab arm vs 6% of the CIT arm, more than half of which were attributed to COVID-19 (fatal COVID-19, 9% vs 3%).

The most common TEAEs reported in at least 20% of patients in the epcoritamab and CIT arms included cytokine release syndrome (53%; N/A), COVID-19 (37%; 12%), neutropenia (36%; 46%), pyrexia (26%; 13%), anemia (26%; 35%), injection site reactions (22%; N/A), diarrhea (20%; 13%), thrombocytopenia (18%; 53%), and nausea (14%; 31%).

Fox noted higher rates of grade 3 or 4 infections with epcoritamab vs CIT, at 30% and 12%, respectively. He added that febrile neutropenia occurred in 2% and 5% of patients, respectively. Moreover, immune effector cell–associated neurotoxicity syndrome was reported in 9 epcoritamab-treated patients (grade 1/2: n = 7; grade 3/4: n = 2).

Fox concluded that the observed toxicities were consistent with the established safety profile of epcoritamab.

Disclosures: Fox reported serving on consultancy or advisory boards for AbbVie, Arvinas, AstraZeneca, Autolus, BMS, Genmab, Incyte, Kite/Gilead, Ono/Deciphera, Roche, SERB, and SOBI; participating in educational activities for AbbVie, Kite/Gilead, Janssen, and Roche; and receiving research funding from AbbVie, BeiGene, Genmab, and Incyte.

References

1. Fox CP, Inchiappa L, Ferhanoğlu B, et al. Results from EPCORE DLBCL-1: randomized phase 3 study of epcoritamab vs investigator’s choice chemoimmunotherapy in patients with relapsed/refractory large B-cell lymphoma. Presented at: 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S235.
2. Sehn LH, Salles G. Diffuse large B-cell lymphoma. N Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612
3. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. doi:10.1182/blood-2017-03-769620
4. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. FDA. May 19, 2023. Accessed June 13, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell