The bispecific antibody odronextamab plus standard CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) chemotherapy yielded robust and durable responses in treatment-naive patients with diffuse large B-cell lymphoma (DLBCL), based on the first results of the phase III OLYMPIA-3 study presented at the 2025 American Society of Hematology Annual Meeting & Exposition (ASH) by Jean-Marie Michot, MD, from Institute Gustave Roussy in France.¹

“The preliminary efficacy was compelling, especially for the odronextamab dose of 160 mg, with a complete remission rate of 100%,” said Dr. Michot.“The data from part 1A of OLYMPIA-3 [the dose escalation phase] suggest that with combining odronextamab and CHOP in previously untreated patients with DLBCL, rituximab is not required to obtain complete remission.”

Preliminary results in 22 patients found the objective response rate to be 78% with 80 mg/week plus CHOP and 100% with 160 mg/week, with complete responses achieved by 44% and 100%, 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 plus CHOP with rituximab plus CHOP.

Odronextamab is a human, IgG4-based CD20 x CD3 bispecific antibody that simultaneously engages T cells and malignant B cells, enabling T-cell-mediated cytotoxicity independent of T-cell/MHC interaction. It has demonstrated strong efficacy in relapsed/refractory DLBCL, and exhibits competitive binding with rituximab for the CD20 epitope in nonclinical studies, he said.

During the question-and-answer period, Dr. Michot elaborated on the potential of the regimen: “It’s the spirit of this study to potentially replace rituximab with a bispecific. We have observed that odronextamab demonstrates compelling efficacy in patients refractory to, or relapsing after, rituximab and after many lines of treatment in the post-CAR-T setting. Notably, odronextamab is potentially superior to rituximab, and the design of the study is to explore the potential for superiority in the frontline setting.”

About OLYMPIA-3

The open-label study was designed with two parts. In part 1, the dose of odronextamab was escalated and optimized. Standard CHOP was given on day 1 of a 21-day cycle; 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 given weekly and then every 2 weeks. Data were reported for 80 and 160 mg given weekly for six total cycles.Part 2 of the study will continue CHOP with patients randomly assigned to receive odronextamab (Odro-CHOP) or rituximab (R-CHOP).

The study assigned 9 previously untreated patients to the 80-mg dose and 13 to the 160-mg dose. Across all of part 1, all patients had de novo DLBCL with high-risk features. Median age was 66 years, with 32% of patients ≥ 75 years old. Most patients (85%) had ECOG performance status 0-1 and the primary cell of origin was non-germinal center B-cell (59%). The International Prognostic Index (IPI) score was 3 for 36% and 4-5 for 27%, and the Lugano stage was III-IV for 95% of patients.

At the time of the analysis, seven (77.8%) patients enrolled at the 80-mg dose had completed cycles one to six, while the remaining two patients had discontinued early (by physician decision). In the 160-mg arm, all 13 patients had completed cycle one, 84.6% had completed cycle six, and two patients discontinued early (physician decision). The relative dose intensity was 87% in the 80-mg group and 77% in the 160-mg group, “indicating that the addition of odronextamab did not impact the exposure to the CHOP backbone,” Dr. Michot noted. Additionally, he reported, “There were few dose reductions of odronextamab and no permanent treatment discontinuations due to adverse events related to odronextamab.”

Additional Odronextamab Efficacy Findings

The median follow-up was 9.2 months for the 80-mg dose group and 7.8 months for the 160-mg group. All patients receiving 160 mg achieved complete responses by end of treatment. Most responses remained ongoing, indicating durability of the complete responses, he said.

In a biomarker analysis, B cell counts declined quickly following the initiation of therapy and were completely cleared after the first dose of odronextamab. T-cell margination was similar to that previously reported with odronextamab monotherapy; on-treatment T-cell counts were comparable between the two dose levels.

Odronextamab Safety Profile

Grade ≥ 3 treatment-emergent adverse events were experienced by all patients treated with the 80-mg and 160-mg doses of odronextamab. Those leading to treatment interruptions or delays were observed in 66.7% and 84.6%, respectively. No dose-limiting toxicities were documented.

Across both doses, the most common treatment-related adverse events were neutropenia (77.3%), cytokine release syndrome (CRS) (54.5%), and anemia (45.5%). The cases of neutropenia were all grade 3 or 4, as were half the cases of anemia. In the discussion period, Dr. Michot indicated that most patients received growth factor support.Thrombocytopenia occurred in 22.7% of patients, almost all grade
3 or 4.

CRS cases, on the other hand, were solely grade 1 (40.9%) or 2 (13.6%) in severity. To manage CRS, tocilizumab was administered to 27.3% of patients and steroids to 18.2%. CRS mostly occurred during the step-up dosing phase at the lowest dose, at a median time to onset of 9 hours and a median duration of 3.8 months. There were no cases of immune effector cell–associated neurotoxicity syndrome or tumor lysis syndrome.

Infections developed in 81.8% of patients treated across both levels. Of these, 31.8% were grade 3 and 9.1% were grade 4. Opportunistic infections were diagnosed in 50% of patients, only one being grade ≥ 3 and the most common being reactivation of or reinfection with cytomegalovirus, COVID-19, and oral candidiasis. 

DISCLOSURE: Dr. Michot had personal financial relationships with MSD, GSK, Ideogen, Gilead, Mallinckrodt Pharmaceuticals, and Regeneron.

REFERENCE

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. 2025 ASH Annual Meeting & Exhibition. Abstract 65. Presented December 6, 2025.

EXPERT POINT OF VIEW

The ASCO Post asked session moderator J. Erika Haydu, MD, PhD, Assistant Professor of Medicine and physician within the Lymphoma Group at Mass General Brigham Cancer Institute, for her thoughts on the OLYMPIA-3 findings for odronextamab-CHOP.¹

One question was, with an ever-expanding number of regimens coming to the clinic for treatment-naive patients with DLBCL, what does odronextamab bring to the table and how would she position its use? “While R-CHOP [rituximab plus cyclophosphamide, vincristine, doxorubicin, prednisone] and pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, liposomal doxorubicin, prednisone] are effective, the incorporation of bispecific antibodies and/or antibody-drug conjugates into upfront regimens has the potential to increase large B-cell lymphoma cure rates,” she said.

J. Erika Haydu, MD, PhD

“At the same time, as the landscape in large B-cell lymphoma continues to rapidly evolve, defining the ‘standard of care’ can be a moving target, and thus choosing the relevant control arm for front-line randomized phase III trials evaluating these novel combinations in such a fast-paced research environment is challenging. If multiple front-line large B-cell lymphoma regimens are ultimately available, in addition to efficacy, factors including logistics, agent availability and cost, and toxicity profiles will also play a role in prescribing patterns,” Dr. Haydu indicated.

To that end, she addressed issues some attendees saw as safety concerns with odronextamab, putting the safety profile in context with other novel agents. “The rate of neutropenia in this study was high (77%), however, it was similar to that observed with epcoritamab [-bysp]-R-CHOP (70%),” she pointed out. “It would be helpful to know the rate of febrile neutropenia with odronextamab-CHOP to further understand the neutropenia risks. It is likely this regimen would warrant prophylactic growth factor if approved.”

“Infections are another important toxicity consideration with bispecific antibodies, and while the rate of grade ≥ 3 infections with odronextamab-CHOP was 41% there were no fatal infections. Cytokine release syndrome (CRS) occurred in 55%, all low grade, and most commonly with the first dose of odronextamab. This CRS rate is similar to what was previously reported for epcoritamab-R-CHOP. Interestingly, the rates of neutropenia and CRS are lower with glofitamab-CHOP or glofitamab-pola-R-CHP, although, of course, cross-trial comparisons are complicated. Ultimately, the toxicity profile of odronextamab-CHOP is within the realm of what would be expected but bears watching with further development,” she commented.

In the not-too-distant future, clinicians may have options on the table for this subset of patients typically seen as challenging. “I am hopeful for an era of precision medicine where readily available tests help guide the most effective treatment for a given lymphoma,” Dr. Haydu said. 

DISCLOSURE: Dr. Haydu has served as a consultant for ADCT, AstraZeneca, Pfizer, and Genmab; and has received research funding from Genmab.

REFERENCE

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. 2025 ASH Annual Meeting & Exhibition. Abstract 65. Presented December 6, 2025.