Odronextamab Plus CHOP Produces Deep, Potentially Durable Responses in Previously Untreated DLBCL

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 American Society of Hematology 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 (cyclophosphamide, doxorubicin, prednisone, and vincristine) and 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 had not yet been 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, which compared 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, of Institut Gustave Roussy in Villejuif, France, 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 odronextamab dose was escalated and optimized. Standard CHOP was given on days 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 or rituximab (R-CHOP).

Across part 1, patient median age was 66 years (range, 24-81), with nearly one-third being 75 years and older (32%). ECOG performance status was 0 in 40% of patients, 1 in 45%, and 2 in 14%. The primary cell of origin was non–germinal center B-cells (59%), and all patients had de novo DLBCL. The International Prognostic Index score was 3 for 36% and 4 or 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 receiving the 80-mg dose had completed cycles 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," Michot said. "There were few dose reductions of odronextamab and no permanent treatment discontinuations due to TEAEs [treatment-emergent adverse events (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 taking the 80-mg dose and 7.8 months for those taking the 160-mg dose. At the assessment, most responses continued to be 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 in B cell counts following CHOP administration, with complete clearance of B cells observed upon initiation of odronextamab.

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

Odronextamab Safety Profile in OLYMPIA-3

Grade 3 or higher 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 in 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 arm.

No patients in the 80-mg arm and one in the 160-mg arm experienced an odronextamab dose reduction due to a TEAE. Dose reductions in CHOP due to TEAEs were needed for 1 patient in the 80-mg group and 5 in the 160-mg group. TEAEs led to treatment discontinuation for 1 patient in each arm. A TEAE led to 1 death in the 160-mg arm. "Of note, there were no dose-limiting toxicities reported," Michot said.

Across both doses, the most common TEAEs were 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 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 to 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% of the infections were grade 3, and 9.1% were grade 4. Opportunistic infections were experienced by 50% of patients, of which only 1 case was grade 3 or higher. The most commonly reported events were cytomegalovirus infection or reinfection (27% for both), as well as COVID-19 and oral candidiasis (18% for each).

Odronextamab Regulatory History and Further Study

In August 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 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 2025 noted concerns with site inspections completed at a plant run by Catalent Indiana LLC.

Odronextamab is being investigated in 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) investigating odronextamab plus lenalidomide for follicular lymphoma.

References

1. Michot JM, 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(suppl 1):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