Category: 3. Business

Treatment with fixed-duration epcoritamab-bysp (Epkinly) plus dose-attenuated rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-mini-CHOP) appeared to be well tolerated and elicited responses in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), according to data from arm 8 of the phase 1/2 EPCORE NHL-2 trial (NCT04663347).¹

The data, which were presented at the 2025 ASH Annual Meeting, showed that at a median follow-up of 33.4 months (range, 2.8-41.1), the overall response rate (ORR) in all patients (n = 28) 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 (range, 1.1-2.7) and the median time to CR was 1.6 months (range, 1.2-8.1).

At 2 years, 79% (95% CI, 57%-91%) of patients remained in response to treatment with the regimen, and 79% (95% CI, 57%-91%) 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 2-year progression-free (PFS) and overall survival (OS) rates were 76% (95% CI, 54%-89%) and 82% (95% CI, 62%-92%), 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 September 21, 2025. At the first assessment, which was done on day 1 of cycle 3, 80% (n = 16) of patients achieved MRD negativity. Of the 4 MRD-positive patients at this assessment, 3 converted to MRD negativity by the second assessment, which was done on day 1 of cycle 6; 2 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, [epcoritamab] may have a role in the treatment of patients with historically poor outcomes,” Chan Cheah, MD, of the Sir Charles Gairdner Hospital and the University of Western Australia, in Nedlands, Australia, said during a presentation of the data.

Why add epcoritamab 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 epcoritamab 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 (NCT05660967 ) indicated that single-agent epcoritamab induced durable responses in patients with newly diagnosed large B-cell lymphoma and comorbidities.² Other findings from EPCORE NHL-2 showed that the combination of epcoritamab 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.³ At the meeting, Cheah shared follow-up data from EPCORE NHL-2.¹

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 epcoritamab at a dose of 48 mg once weekly for cycles 1 and 2 and every 3 weeks for cycles 3 to 6 and intravenous R-mini-CHOP, which comprised 375 mg/m² of rituximab, 400 mg/m² of cyclophosphamide, 25 mg/m² of doxorubicin, 1 mg/m² of vincristine—all given every 3 weeks—and 100 mg/day of prednisone, given on days 1 to 5 of each cycle from cycles 1 to 6. Epcoritamab was then given at 48 mg every 4 weeks for cycles 7 to 8.

ORR by investigator assessment served as the primary end point of the trial. Secondary end points included CR rate, duration of response, duration of CR, PFS, OS, MRD negativity, and safety.

In terms of baseline characteristics, the median patient age was 81 years (range, 74-90). 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 epcoritamab in this population?

Cheah noted that most adverse effects (AEs) were mild to moderate in severity, and no new safety concerns associated with the addition of epcoritamab to R-mini-CHOP presented with longer follow-up. The most frequent grade 3 or higher treatment-emergent adverse effects (TEAEs) were neutropenia (43%), serious infections (32%), and anemia 14%). Most grade 3 or higher serious infections were reported within the first 6 cycles of treatment, when R-mini-CHOP was being coadministered.

The most common TEAE was cytokine release syndrome (CRS), which occurred in 61% of patients; this effect was grade 1 for 32% of patients and grade 2 for 29% of patients. Time to first onset of CRS occurred at a median of 16 days (range, 8-17). Patients were treated with either tocilizumab (Actemra; 29%) or corticosteroids (14%), leading to CRS resolution across all patients affected. The median time to resolution was 2 days (range, 1-7). CRS led to treatment discontinuation in 1 patient. Cheah noted that almost all (90%) CRS events occurred in cycle 1 of treatment.

Additional common TEAEs 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 epcoritamab in 3 patients (11%), including 1 fatal event, and discontinuation of R-mini-CHOP in 6 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 epcoritamab plus R-mini-CHOP are encouraging,” Cheah stated in a news release issued by Genmab.⁴ “These results, along with those from other arms of the trial, support the potential for combinations of epcoritamab with standard of care treatment across a range of disease settings and patient populations.”

References

1. Cheah C, Ďuraš J, Belada D, et al. 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. Presented at: 2025 ASH Annual Meeting; December 6-9, 2025; Orlando, FL. Abstract 64.
2. 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. Presented at: 2025 ASH Annual Meeting; December 6-9, 2025; Orlando, FL. Abstract 63.
3. Leslie LA, Cheah CY, Morschhauser F, et al. 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. Blood. 2024;144(suppl 1):3106. doi: 10.1182/blood-2024-199652
4. Genmab press release. 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. Genmab. December 6, 2025. Accessed December 6, 2025. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-data-multiple-clinical-trials-showing-treatment

The CD20 × CD3-directed bispecific antibody odronextamab produced high, potentially durable complete responses (CR) and had a generally manageable safety profile when administered in combination with standard CHOP chemotherapy to patients with previously untreated diffuse large B-cell lymphoma (DLBCL) and high-risk features, according to initial results from part 1 of the phase 3 OLYMPIA-3 study (NCT06091865).¹

Data presented during the 2025 ASH Annual Meeting and Exposition showed that the objective response rate (ORR) with this rituximab (Rituxan)–free regimen was 78% with the weekly 80 mg dose of odronextamab plus CHOP and was 100% for the weekly 160 mg dose of odronextamab plus CHOP. The complete response rates were 44% and 100% for each dose, respectively. The median duration of response, duration of complete response, and progression-free survival were not yet reached at the early analysis. Based on the combination of efficacy and safety, the 160 mg dose of odronextamab was selected for further investigation in the randomized portion of the study comparing the bispecific with rituximab.

“Data from part 1a of OLYMPIA-3 suggest that when combining odronextamab with CHOP in previously untreated patients with DLBCL, rituximab was not required to achieve deep and durable responses,” lead investigator Jean-Marie Michot, MD, from Institute Gustave Roussy, said during a presentation of the results. “The safety profile of fixed duration odronextamab-CHOP treatment was generally manageable in patients with previously untreated DLBCL with high-risk features, with no new safety signals compared with previous reports.”

OLYMPIA-3 Study Design and Patient Characteristics

The open-label study was designed with 2 parts. In part 1, the dose of odronextamab was escalated and optimized. Standard CHOP was given on day 1 and 8 of each cycle and odronextamab was administered starting on day 8, initially at a step-up dose of 0.7/4/20 mg and then at varying dose levels including 80 mg or 160 mg weekly and 160 mg and 320 mg every 2 weeks, with data only available for the weekly doses. Part 2 of the study will continue CHOP with patients randomly assigned to receive odronextamab (Odro-CHOP) or rituximab (R-CHOP).

Across all of part 1, the median age of patients was 66 years (range, 24-81), with nearly a third aged 75 or older (32%). ECOG performance status was 0 (40%), 1 (45%), and 2 (14%). The primary cell of origin was non-GCB (59%), and all patients had de novo DLBCL. IPI score was 3 for 36% and 4 to 5 for 27% of patients. The Lugano stage was III to IV for 95% of patients.

At the time of the analysis, 77.8% of patients enrolled to the 80 mg dose had completed cycle 1 to 6 (7 of 9). The remainder of patients in this group had discontinued early, due to physician decision (n = 2). In the 160-mg arm (n = 13), all patients had completed cycle 1 and 84.6% had completed cycle 6. Two discontinued early due to physician decision. The relative dose intensity was 87% in the 80-mg group and 77% in the 160-mg group.

“Most patients completed 6 cycles of odronextamab-CHOP at both dose levels,” said Michot. “There were few dose reductions of odronextamab and no permanent treatment discontinuations due to TEAEs related to odronextamab. There were no clinically important differences in safety between dose levels.”

Additional Odronextamab Efficacy Findings

The median duration of follow-up was 9.2 months for those enrolled in the 80 mg dose and was 7.8 months for those in the 160 mg dose. At the assessment, most responses remained ongoing. “CRs appeared durable,” Michot said.

In a biomarker analysis, B cell counts declined quickly following the initiation of therapy. There was an initial drop with CHOP administration, with B cells being completely cleared with the initiation of odronextamab.

There was slight T cell margination following the initiation of therapy, but these were transient and like prior reports with odronextamab, Michot said. T cell findings were similar for each dose.

Odronextamab Safety Profile in OLYMPIA-3

Grade 3 or higher treatment emergent adverse events (TEAEs) were experienced by all patients treated with the 80 mg and 160 mg doses of odronextamab. Serious TEAEs were seen in 77.8% of those treated with the 80 mg dose and for 92.3% of those administered the 160 mg dose. TEAEs led to treatment interruption or delay for 66.7% of those in the 80-mg arm and for 84.6% of those in the 160-mg group.

TEAE led to an odronextamab dose reduction for no patients in the 80 mg-arm and for 1 in the 160-mg group. Dose results in CHOP due to TEAEs were needed for 1 patient in the 80-mg group and for 5 in the 160-mg group. TEAEs led to treatment discontinuation for 1 patient in each dose level arm. There was 1 TEAE that led to death in the 160-mg arm. “Of note, there were no dose-limiting toxicities reported,” Michot said.

Across both doses, the most common TEAE was neutropenia (81.8%), cytokine release syndrome (CRS; 54.5%), anemia (45.5%), and nausea (40.9%). The most common treatment-related adverse events were similar with neutropenia seen in 77.3% of patients, CRS in 54.5%, anemia in 45.5%, and nausea in 36.4%.

CRS was solely grade 1/2 in severity, with 40.9% of patients having a grade 1 event and 13.6% having a grade 2 event. Tocilizumab was administered to manage CRS for 27.3% of patients and steroids were given for 18.2%. The median CRS duration was 3.8 months and the median time to onset was 9 hours. CRS mostly occurred during the step-up dosing phase at the lowest dose of 0.7 mg, after this initial step-up the rates of CRS were low. There were no cases of immune effector cell–associated neurotoxicity syndrome or tumor lysis syndrome.

Infections were seen in 81.8% of patients treated across both levels. Of these, 31.8% were grade 3 in severity and 9.1% were grade 4. Opportunistic infections were experienced by 50% of patients, of which only 1 patient had a grade 3 or higher opportunistic infection. The most commonly reported events were CMV infection or reinfection (27% for both) or COVID-19 and oral candidiasis (18% for each).

Odronextamab Regulatory History and Further Study

In August of 2025, the FDA issued a complete response letter (CRL) for a biologics license application for odronextamab for the treatment of relapsed/refractory follicular lymphoma following 2 or more lines of systemic therapy.² Additionally, in March of 2024,³ the agent received 2 CRLs for DLBCL and follicular lymphoma. In both cases, the applications were based on phase 2 findings. The CRL issued in August noted concerns with site inspections completed at a plant ran by Catalent Indiana LLC.

Odronextamab is the subject of several clinical trials across several disease settings, either as monotherapy or in various combination regimens, including the phase 3 OLYMPIA-2 study (NCT06097364) for follicular lymphoma and the phase 3 OLYMPIA-5 study (NCT06149286) looking at odronextamab plus lenalidomide for follicular lymphoma.

References

1. Michot J-M, Yagci M, Kargus K, et al. Odronextamab plus chemotherapy in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): First Results from part 1 of the Phase 3 Olympia-3 study. Blood. 2025;146 (Supplement 1):abstract 65. doi:10.1182/blood-2025-65
2. Regeneron Reports Second Quarter 2025 Financial and Operating Results. News release. Regeneron. August 1, 2025. Accessed December 6, 2025. https://tinyurl.com/bdz4e7ex
3. Regeneron provides update on biologics license application for odronextamab. News release. Regeneron. March 25, 2024. Accessed December 6, 2025. https://tinyurl.com/mr2w4j8x

Treatment with the hepcidin mimetic rusfertide continued to demonstrate sustained hematocrit control below 45% and high rates of phlebotomy ineligibility through week 52 for patients with polycythemia vera (PV), according to updated findings from the phase 3 VERIFY study (NCT05210790) presented at the 2025 ASH Annual Meeting.¹

For those who crossed over from placebo to rusfertide, there was a rapid and durable drop in their hematocrit levels within the first 4 weeks. Both groups had similar levels of hematocrit control by week 52, regardless of having received a placebo or rusfertide in the first part of the study. For those continuing rusfertide from part 1a of the study to part 1b, the response rate, defined as absence of phlebotomy eligibility, went from 76.9% to 84.1%. For those who switched from placebo in part 1a to rusfertide in part 1b, the response went from 32.9% to 77.9%.

“Rusfertide met the primary and all 4 secondary end points in VERIFY from baseline to week 32 and continued to provide durable, sustained control of hematocrit below 45% and phlebotomy ineligibility through week 52,” lead investigator Andrew Kuykendall, MD, at Moffitt Cancer Center in the Department of Malignant Hematology, said during a presentation of the results. “After 52 weeks of treatment in VERIFY, rusfertide was well tolerated with a safety profile that was consistent with prior observations.”

What is the study design of VERIFY?

The phase 3 study was broken into several parts. In part 1a, patients were randomly selected to receive the current standard of care plus rusfertide (n = 147) or placebo (n = 146) for 32 weeks, with primary end points assessed at weeks 20 to 32. After this initial period, patients in the placebo group crossed over to receive rusfertide plus standard of care. This open-label part of the study (part 1b; n = 274) continued until week 52, at which point the durability of response was assessed. Standard of care was defined as phlebotomy with or without cytoreductive therapy. Subsequent parts of the study are ongoing to assess long-term safety. Results from ASH were for Part 1b.

Baseline characteristics were balanced between groups in part 1a of the study, Kuykendall noted. In part 1b, the median age was 57 years, and most patients were male (72.6%). Nearly half of patients had high-risk PV (44.9%), which was defined as having a prior thromboembolic event and/or age 60 or older. The median age at PV diagnosis was 51 years, and the median PV duration was 2.9 years.

Nearly half of patients were not on a cytoreductive therapy for part 1b of the study (44.9%), which was consistent with part 1a. For those on therapy, the most common was hydroxyurea (38.3%), followed by interferons (13.9%). There was a small subset of patients on ruxolitinib (2.6%; Jakafi).

What were the results from part 1a of the VERIFY study?

In part 1a of the study, rusfertide was superior to placebo across all key end points. For placebo and rusfertide, respectively, the response rates were more than doubled (32.9% vs 76.9%; P <.0001), and 62.6% of those on rusfertide had a hematocrit lower than 45% compared with 14.4% for placebo (P <.0001). There were fewer (P <.0001) mean phlebotomies required with rusfertide (n = 0.5) compared with placebo (n = 1.8).

In addition to clinical end points, patient-reported outcomes were also superior with rusfertide. For the PROMIS fatigue SF-8a T-score, there was a 0.17 increase at week 32 with placebo compared with a decline of 1.78 for rusfertide, suggesting less fatigue (-1.95 delta; P = .0268). Improvement was also seen in Myelofibrosis Symptom Assessment Form Version 4.0 Total Symptom Score 7 Items, with a 0.54 drop with placebo and a 2.40 drop for rusfertide (-1.87 delta; P = .0239).

What were the new rusfertide findings from part 1b of VERIFY?

The median time to phlebotomy was not reached in the rusfertide arm compared with 16 weeks in the placebo group for part 1a. In part 1b, the median time to phlebotomy was not estimable in both arms. “Once patients switched from placebo to rusfertide, time to first phlebotomy looked similar in both groups,” Kuykendall said.

Ferritin levels normalized over time for those receiving rusfertide, with a continued improvement seen with rusfertide throughout the course of the study. There was no change with placebo in part 1a but a consistent climb in ferritin once patients crossed over to received rusfertide. There was only a small change in serum iron levels in both groups of patients (from ~6 µm ol/L at baseline increasing to ~10 µm ol/L). Transferrin levels decreased with rusfertide while transferrin saturation increased. As with all levels, a significant shift could be seen with patients moved from placebo to rusfertide.

“Rusfertide lowered hematocrit levels without exacerbating systemic iron deficiency,” added Kuykendall.

There was a modest improvement in mean corpuscular volume levels with rusfertide. Leukocytes counts were stable in both arms with a slight increase, and an improvement in platelet counts was seen with rusfertide.

What was the safety profile for rusfertide in VERIFY?

At the data cutoff, 86.7% of patients continued to receive open-label rusfertide, with discontinuations being uncommon, Kuykendall said. In part 1a, just 7.5% of patients discontinued rusfertide due to adverse events (AEs; n = 8) or study withdrawal (n = 3). This compares with a discontinuation rate of 4.1% in the placebo group for AEs (n = 5) and disease progression (n = 1). In part 1b, the discontinuation rate was 2.6%, with 3 from AEs, 2 from lack of efficacy, 1 for other reasons, and 1 for study withdrawal.

In part 1a, there were fewer secondary cancer events in the rusfertide group compared with placebo (3 vs 8, respectively). In part 1b, those who switched from placebo had 2 cancer events compared with 4 in the arm that was on rusfertide for both part 1a and 1b.

Most AEs were grade 1 or 2 in severity, with at least 1 treatment-emergent adverse events (TEAEs) occurring in 86.3% of those in the placebo group and for 90.3% of those in the rusfertide group in part 1a. In part 1b, TEAE rates were similar between groups at approximately 75%. The most common grade 3 TEAE were anemia, asthenia, and hypertension, Kuykendall noted. These occurred in 3 patients each. Serious AEs were experienced by 3.4% of patients in part 1a and by 2.6% in part 1b.

In part 1a of the study, injection site reactions occurred in 32.9% of those in the placebo group and in 55.9% in the rusfertide group. In part 1b, infusion site reactions were seen in 32.9% of those in the crossover group and for 9.7% in the rusfertide arm.

“Optimistically, you can see that some of the injection site reactions actually go down in the rusfertide arm from week 32 to 52, suggesting it may lessen over time,” Kuykendall said.

What are the next steps for rusfertide?

A regulatory submission is being planned for rusfertide as a treatment for patients with PV. Data for the submission will come from the VERIFY study along with results from the REVIVE study (NCT04057040). In the REVIVE study,² the response rate with rusfertide was 60% compared with 17% for placebo (P = .002).

Parts 2 and 3 of the VERIFY study will continue to assess long-term efficacy and safety for rusfertide, with part 2 scheduled to go to week 156 and part 3 expending from the end of part 2 through the end of treatment.

References

1. Kuykendall A, Bankar A, Pettit K, et al. Rusfertide or placebo plus current standard-of-care therapy for polycythemia vera: Durability of response and safety results through week 52 from the randomized controlled phase 3 VERIFY study. Blood. 2025;146(suppl 1): 81. doi:10.1182/blood-2025-8
2. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med. 2024;390(8):723-735. doi:10.1056/NEJMoa2308809