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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