Older Patients With DLBCL May Benefit From First-Line Epkinly Plus R-mini-CHOP

Among older patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), treatment with fixed-duration Epkinly (epcoritamab-bysp) plus dose-attenuated Rituxan (rituximab) plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-mini-CHOP) appeared to be well tolerated and elicited responses, clinical trial data have shown.

Data from arm 8 of the phase 1/2 EPCORE NHL-2 trial, which were presented at the 2025 ASH Annual Meeting, showed that at a median follow-up of 33.4 months, the overall response rate (ORR) in all patients (28 patients) was 93%, which was comprised of a complete response (CR) rate of 86% and a partial response (PR) rate of 7%. The median time to response was 1.4 months and the median time to CR was 1.6 months.

At two years, 79% of patients remained in response to treatment with the regimen, and 79% remained in CR. Of the 22 patients who completed therapy, 20 experienced a CR at the end of treatment (91%). At a median follow-up of 22.6 months after the end of treatment, 90% of the 20 patients remained in CR. Moreover, the two-year progression-free (PFS) and overall survival (OS) rates were 76% and 82%, respectively. The median PFS and OS were not reached irrespective of International Prognostic Index score.

Of the 21 patients evaluable for minimal residual disease (MRD), 20 (95%) were negative at the time of the data cutoff date of Sept. 21, 2025. At the first assessment, which was done on day 1 of cycle 3, 80% (16) of patients achieved MRD negativity. Of the four MRD-positive patients at this assessment, three converted to MRD negativity by the second assessment, which was done on day 1 of cycle 6; two patients experienced subsequent progressive disease. Notably, MRD negativity was observed across all patient subgroups, including bulky disease (89%) and those with an IPI score ranging from 3 to 5 (93%).

“We can conclude that in combination with dose-attenuated chemotherapy, [Epkinly] may have a role in the treatment of patients with historically poor outcomes,” Dr. Chan Cheah, of the Sir Charles Gairdner Hospital and the University of Western Australia, in Nedlands, Australia, said during a presentation of the data.

Why add Epkinly to R-mini-CHOP?

Although R-mini-CHOP is the standard of care (SOC) for patients with newly diagnosed DLBCL who are not able to receive the full dose, outcomes with the regimen remain suboptimal, Cheah explained. “It’s clear that better options for these patients are required,” he added. Previously, the CD3xCD20 bispecific antibody Epkinly was found to be efficacious when administered as a monotherapy or paired with SOC in those with newly diagnosed DLBCL.

For example, findings from the phase 2 EPCORE DLBCL-3 trial indicated that single-agent Epkinly induced durable responses in patients with newly diagnosed large B-cell lymphoma and comorbidities. Other findings from EPCORE NHL-2 showed that the combination of Epkinly and R-mini-CHOP elicited an ORR of 89% and a CR rate of 82% in elderly patients with newly diagnosed DLBCL who could not receive the full dose of R-CHOP. At the meeting, Cheah shared follow-up data from EPCORE NHL-2.

What did EPCORE NHL-2 evaluate?

The open-label, phase 1b/2 trial enrolled patients with newly diagnosed DLBCL, which could have been DLBCL not otherwise specified, T-cell or histocyte-rich DLBCL, high-grade B-cell lymphoma, or grade 3B follicular lymphoma. Patients had an ECOG performance status ranging from 0 to 2 and could not be eligible to receive full-dose R-CHOP because they were 75 years of age or older or 65 years of age or older with a comorbidity.

Twenty-eight patients received a fixed duration of subcutaneous Epkinly at a dose of 48 mg once weekly for cycles 1 and 2 and every three weeks for cycles 3 to 6 and intravenous R-mini-CHOP, which comprised 375 mg/m² of Rituxan, 400 mg/m² of cyclophosphamide, 25 mg/m² of doxorubicin, 1 mg/m² of vincristine — all given every three weeks — and 100 mg/day of prednisone, given on days 1 to 5 of each cycle from cycles 1 to 6. Epkinly was then given at 48 mg every four weeks for cycles 7 to 8.

In terms of baseline characteristics, the median patient age was 81 years. Patients were not eligible to receive a full dose of anthracycline because of age older than 75 years (96%), hypertension requiring treatment (54%), diabetes mellitus (11%) or history of myocardial infarction (4%). Moreover, 43% of patients had an IPI score of 4 to 5 at screening, 39% had a bulky tumor of 7 cm or larger, and the majority had elevated lactate dehydrogenase (64%).

What was the safety profile of Epkinly in this population?

Cheah noted that most side effects were mild to moderate in severity, and no new safety concerns associated with the addition of Epkinly to R-mini-CHOP presented with longer follow-up. The most frequent grade 3 (severe) or higher treatment-emergent side effects were neutropenia (43%), serious infections (32%) and anemia 14%). Most grade 3 or higher serious infections were reported within the first six cycles of treatment, when R-mini-CHOP was being coadministered.

The most common treatment-emergent side effect was cytokine release syndrome (CRS), which occurred in 61% of patients; this effect was grade 1 (mild) for 32% of patients and grade 2 (moderate) for 29% of patients. Time to first onset of CRS occurred at a median of 16 days. Patients were treated with either Actemra (tocilizumab; 29%) or corticosteroids (14%), leading to CRS resolution across all patients affected. The median time to resolution was two days. CRS led to treatment discontinuation in one patient. Cheah noted that almost all (90%) CRS events occurred in cycle 1 of treatment.

Additional common treatment-emergent side effects occurring in 20% or more patients were neutropenia, serious infections, anemia, constipation, fatigue, hypokalemia and fall. No patients experienced immune effector cell–associated neurotoxicity syndrome (ICANS) or tumor lysis syndrome (TLS).

TEAEs led to discontinuation of Epkinly in three patients (11%), including one fatal event, and discontinuation of R-mini-CHOP in six patients (21%).

What is the significance of the updated EPCORE NHL-2 data?

“Despite an older population of newly diagnosed diffuse large B-cell lymphoma, the outcomes observed in arm 8 of the EPCORE NHL-2 evaluating fixed-duration Epkinly plus R-mini-CHOP are encouraging,” Cheah stated in a news release issued by Genmab. “These results, along with those from other arms of the trial, support the potential for combinations of Epkinly with standard of care treatment across a range of disease settings and patient populations.”

References

1. “Epcoritamab + R-mini-CHOP results in 2-year remissions and high MRD negativity rates in elderly patients with newly diagnosed DLBCL: Results from the EPCORE NHL-2 trial” by Dr. Chan Cheah et al., presented at: 2025 ASH Annual Meeting; Dec. 6 to 9, 2025; Orlando, Florida. Abstract 64.
2. “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” by Dr. Umberto Vitolo et al., presented at: 2025 ASH Annual Meeting; December 6 to 9, 2025; Orlando, Florida. Abstract 63.
3. “Fixed-duration epcoritamab + R-mini-CHOP in patients with previously untreated diffuse large B-cell lymphoma ineligible for full-dose R-CHOP: Updated results from arm 8 of the Epcore NHL-2 trial,” by Dr. Chan Cheah et al. Blood. 2024;144(suppl 1):3106. doi: 10.1182/blood-2024-199652
4. “Genmab announces data from multiple clinical trials showing treatment with fixed-duration epcoritamab led to remissions in first-line diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL),” news release; https://ir.genmab.com/news-releases/news-release-details/genmab-announces-data-multiple-clinical-trials-showing-treatment

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