Amog patients with previously untreated diffuse large B-cell lymphoma (DLBCL), treatment with the CD20 and CD3 bispecific antibody odronextamab has been associated with early efficacy in combination with standard CHOP chemotherapy.
The first results from a small cohort of patients enrolled in part 1 of the phase 3 OLYMPIA-3 study were presented at the 2025 ASH Annual Meeting.
In the early results, the objective response rate (ORR) was 78% with the weekly 80 milligram dose of odronextamab plus CHOP and was 100% for the weekly 160 milligram 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 milligram dose of odronextamab was selected for further investigation in the randomized portion of the study comparing the bispecific with Rituxan (rituximab).
"Data from part 1a of OLYMPIA-3 suggest that when combining odronextamab with CHOP in previously untreated patients with DLBCL, [Rituxan] was not required to achieve deep and durable responses," lead investigator Dr. Jean-Marie Michot 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 two 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 milligrams and then at varying dose levels including 80 milligrams or 160 milligrams weekly and 160 milligrams and 320 milligrams every two 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 Rituxan(R-CHOP).
Across all of part 1, the median age of patients was 66 years, 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 3 to 4 for 95% of patients.
At the time of the analysis, 77.8% of patients enrolled to the 80 milligram dose had completed cycle 1 to 6 (seven of nine). The remainder of patients in this group had discontinued early, due to physician decision (two patients). In the 160-mg arm (13 patients), 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-milligram group and 77% in the 160- milligram group.
"Most patients completed six cycles of odronextamab-CHOP at both dose levels," said Michot. "There were few dose reductions of odronextamab and no permanent treatment discontinuations due to [treatment-emergent side effects] 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 milligram dose and was 7.8 months for those in the 160 milligram 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 (severe) or higher treatment emergent side effects were experienced by all patients treated with the 80 milligram and 160 milligram doses of odronextamab. Serious treatment emergent side effects were seen in 77.8% of those treated with the 80 milligram dose and for 92.3% of those administered the 160 milligram dose. Treatment emergent side effects led to treatment interruption or delay for 66.7% of those in the 80-milligram arm and for 84.6% of those in the 160-milligram group.
Treatment emergent side effects led to an odronextamab dose reduction for no patients in the 80 milligram arm and for one in the 160-milligram group. Dose reductions in CHOP due to treatment emergent side effects were needed for one patient in the 80-milligram group and for five in the 160-milligram group. Treatment emergent side effects led to treatment discontinuation for one patient in each dose level arm. There was one treatment emergent side effect that led to death in the 160-milligram arm. "Of note, there were no dose-limiting toxicities reported," Michot said.
Across both doses, the most common treatment emergent side effects were neutropenia (81.8%), cytokine release syndrome (CRS; 54.5%), anemia (45.5%) and nausea (40.9%). The most common treatment-related side effects 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 (mild)/2 (moderate) 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 nine 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 (life-threatening). Opportunistic infections were experienced by 50% of patients, of which only one 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 U.S. Food and Drug Adminsitration (FDA) issued a complete response letter (CRL) for a biologics license application for odronextamab for the treatment of relapsed/refractory follicular lymphoma following two or more lines of systemic therapy.Additionally, in March of 2024, the agent received two 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 for follicular lymphoma and the phase 3 OLYMPIA-5 study looking at odronextamab plus lenalidomide for follicular lymphoma.
References:
- “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,” by Dr. Jean-Marie Michot et al., Blood.
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