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Epcoritamab plus R-CHOP delivered durable remissions beyond 3 years across high-risk subgroups of patients with newly diagnosed DLBCL.
The fixed-duration combination of epcoritamab-bysp (Epkinly) and R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) led to sustained remissions and disease-free survival beyond 3 years across key subgroups of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), including those with high International Prognostic Index (IPI) scores, according to data from arm 1 of the phase 1/2 EPCORE NHL-2 study (NCT04663347).1
The data, which were shared during the 2025 ASH Annual Meeting, showed that in all patients (n = 47), the objective response rate (ORR) with the combination was 98%, which comprised a complete response (CR) rate of 85% and a partial response (PR) rate of 13%.
The ORRs in those with an IPI score of up to 3 (n = 29) or 4 to 5 (n = 18) were 100% (CR, 86%; PR, 14%) and 94% (CR, 83%; PR, 11%), respectively. By tumor volume, those with a tumor size of up to 10 cm (n = 31) experienced an ORR of 97% (CR, 84%; PR, 13%), and those with a tumor size larger than 10 cm (n = 16) had an ORR of 100% (CR, 88%; PR, 12%). Moreover, patients up to 60 years of age (n = 20) experienced a 100% ORR (CR, 80%; PR, 20%), and those older than 60 years (n = 27) had an ORR of 96% (CR, 89%; PR, 7%). Those with a Germinal Center B-cell–like cell of origin (n = 29) experienced an ORR of 97% (CR, 79%; PR, 18%), and those with Activated B-cell–like cell of origin (n = 16) had a 100% ORR (CR, 100%).
Ninety-two percent of patients remained in CR at 2 years; at 3 years, this rate was 74%. The median duration of CR was not reached (NR; 95% CI, NR-NR) in all of these clinically relevant subgroups. Progression-free survival (PFS) and overall survival (OS) benefits with the combination were also sustained. The median PFS was NR (95% CI, 38.4-NR) with 80% of patients remaining progression free at 2 years and 69% progression free at 3 years. The median OS was also NR (95% CI, NR-NR), with 87% and 83% of patients remaining alive at 2 and 3 years, respectively. PFS and OS were NR across those key subgroups.
At day 1 of cycle 3, 86% of patients who had available samples were determined to have achieved minimal residual disease (MRD) negativity. Four patients who achieved CR but were still positive for MRD at this time point later converted to negative status and were reported to have long-term responses. Most patients who experienced CR and had available samples achieved sustained MRD negativity.
“These results are promising compared with R-CHOP alone and support further investigation in the ongoing phase 3 EPCORE DLBCL-2 study [NCT05578976] of epcoritamab plus R-CHOP vs R-CHOP in newly diagnosed patients with DLBCL,” Lorenzo Falchi, MD, a medical oncologist and hematologist and assistant attending physician in the Lymphoma Service at Memorial Sloan Kettering Cancer Center, in New York, NY, and colleagues, wrote in a poster of the data.
Although the first-line standard of care for DLBCL is R-CHOP, one-third to one-half of patients with this disease will relapse, and most relapses occur within 1 to 2 years of initial response to treatment. It is known that those with high-risk disease, particularly those with IPI scores of 3 or higher, have poor prognosis and outcomes. In this clinically relevant subgroup, CR rates fall around 50% and PFS rates at 5 years range from about 48% to just 58%. No new regimens since R-CHOP have proven to lead to better OS in the frontline setting, signifying an unmet need. Epcoritamab has showcased efficacy as a single agent and when paired with SOC in patients with frontline DLBCL.2,3
Arm 1 of the trial included patients with newly diagnosed, CD20-positive DLBCL, which could have included DLBCL not otherwise specified, T-cell/histocyte-rich DLBCL, double/triple hit DLBCL, or grade 3B follicular lymphoma. These patients were required to have measurable disease per CT or MRI, an ECOG performance status no higher than 2, acceptable organ function, and an IPI score of at least 3.
A total of 47 patients received fixed-duration epcoritamab with R-CHOP. Epcoritamab was administered subcutaneously at a dose of 48 mg weekly for cycles 1 to 4, every 3 weeks for cycles 5 and 6, and every 4 weeks for up to 1 year for cycles 7 and beyond. The intravenous R-CHOP regimen included rituximab given at 375 mg/m2, cyclophosphamide at 750 mg/m2, doxorubicin at 50 mg/m2, and vincristine at 1.4 mg/m2—all given every 3 weeks—and prednisone at 100 mg on days 1 to 5 of each cycle.
The primary end point was investigator-assessed ORR by Lugano criteria, and key secondary end points comprised CR rate, duration of CR, PFS, OS, and safety. Investigators also examined MRD negativity.
Previous data from the study showed that at a data cutoff date of April 9, 2025, and at a median follow-up of 38.8 months (range, 0.8-44.3), the ORR with epcoritamab plus R-CHOP was 98%, which included a CR rate of 85%.2 High CR rates were reported irrespective of IPI score, with rates ranging from 83% in those with a score of 4 to 5 to 86% in those with a score of 3. Moreover, about 80% of patients remained free of progression, and 87% were still alive at 33 months. It was previously reported that efficacy outcomes were comparable across relevant subgroups of age, tumor size, and cell of origin.
Longer-term follow-up of arm 1 was shared during the 2025 ASH Annual Meeting.1 In the 47 evaluable patients, the median age was 64.0 years (range, 19-82). About half of the patients were male (49%); most were White (79%) and had de novo disease (81%). In terms of performance status, 32% had a status of 0, 55% had a status of 1, and 13% had a status of 2.
More than half of patients had a cell of origin of GCB (62%), and the remainder had ABC/non-GCB (34%). In terms of IPI score at the time of screening, 47% had a score of 3, and 38% had a score of 4 to 5. Tumor volume was smaller than 7 cm for 47% of patients, 7 cm or larger for 53% of patients, up to 10 cm for 66% of patients, and larger than 10 cm for 34% of patients. Sixty-eight percent of patients had elevated lactate dehydrogenase.
The median duration of treatment with epcoritamab was 11.5 months (range, 0.6-13.2), and 94% had completed up to 6 cycles of R-CHOP. Additional data revealed quick and durable reductions in circulating tumor DNA for all key subgroups.
“Safety was consistent with prior reports,” the study authors wrote. Treatment-emergent adverse effects (TEAES) were reported in all patients who received the combination, with 94% of effects being grade 3 or higher; 72% of serious TEAEs were observed. Fifteen percent of patients experienced TEAEs that led to treatment discontinuation, and 4% proved fatal.
The most frequent TEAEs were neutropenia (74%), anemia (72%), and cytokine release syndrome (60%). CRS was grade 1 for 49% of patients, grade 2 for 9% of patients, and grade 3 or 2% of patients, and it was mostly observed in the first cycle of treatment. Cytopenias were mostly experienced during the first 6 months of treatment while R-CHOP was also being given, and subsequently decreased in incidence. Serious and grade 3/4 infections were also mostly observed in the first 6 months of treatment and decreased afterward, with no new epcoritamab-associated infections observed in the post-treatment period. “No new grade 5 AEs were reported [with the longer follow-up,]” the study authors concluded.
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