Unveiling the Potential of Odronextamab Plus CHOP in DLBCL Treatment
A groundbreaking approach to lymphoma treatment? Early findings from a phase 3 trial suggest a promising new strategy for patients with diffuse large B-cell lymphoma (DLBCL). But here's where it gets controversial...
The study, OLYMPIA-3, evaluated the addition of odronextamab, a CD20 × CD3-directed bispecific antibody, to standard CHOP chemotherapy. The results showed impressive complete response rates and a manageable safety profile. Lead investigator Jean-Marie Michot, MD, from Institute Gustave Roussy, highlighted that "data from part 1a of OLYMPIA-3 suggest that when combining odronextamab with CHOP, rituximab was not required to achieve deep and durable responses."
The Study Design and Patient Characteristics
OLYMPIA-3 was an open-label study with two parts. Part 1 focused on dose escalation and optimization of odronextamab. CHOP was administered on days 1 and 8 of each cycle, followed by odronextamab starting on day 8. The doses evaluated were 80 mg and 160 mg weekly. Part 2 of the study will randomize patients to receive either odronextamab (Odro-CHOP) or rituximab (R-CHOP) in combination with CHOP.
The median age of patients across part 1 was 66 years, with a significant proportion (32%) aged 75 or older. The primary cell of origin was non-GCB, and all patients had de novo DLBCL. The Lugano stage was III to IV for most patients (95%).
Response Rates and Safety Profile
The objective response rate (ORR) with the 80 mg dose of odronextamab plus CHOP was 78%, while the 160 mg dose achieved a remarkable 100% ORR. Complete response rates followed a similar trend, with 44% for the 80 mg dose and an impressive 100% for the 160 mg dose. The median duration of response, duration of complete response, and progression-free survival were not yet reached at the early analysis, indicating potentially long-lasting benefits.
In terms of safety, grade 3 or higher treatment-emergent adverse events (TEAEs) were observed in all patients treated with both doses. Serious TEAEs were more frequent in the 160 mg group (92.3%) compared to the 80 mg group (77.8%). TEAEs led to treatment interruptions or delays in a significant proportion of patients. However, there were no permanent treatment discontinuations due to TEAEs related to odronextamab, and no clinically important differences in safety were noted between the dose levels.
Biomarker Analysis and T Cell Findings
A biomarker analysis revealed a rapid decline in B cell counts following therapy initiation. CHOP administration caused an initial drop, and odronextamab cleared B cells completely. There was also slight T cell margination, but these were transient and similar to previous reports with odronextamab. T cell findings were consistent across both doses.
Infections and CRS Management
Infections were common, observed in 81.8% of patients across both dose levels. The majority of these infections were grade 3 in severity (31.8%), with only 9.1% being grade 4. Opportunistic infections were experienced by 50% of patients, but only one patient had a grade 3 or higher opportunistic infection. The most commonly reported events were CMV infection or reinfection (27%) and COVID-19 and oral candidiasis (18% each).
Cytokine release syndrome (CRS) was a notable adverse event, with the most common treatment-related adverse events being neutropenia (77.3%), CRS (54.5%), anemia (45.5%), and nausea (36.4%). CRS was solely grade 1/2 in severity, and tocilizumab and steroids were administered to manage CRS in 27.3% and 18.2% of patients, respectively. The median CRS duration was 3.8 months, and the median time to onset was 9 hours. CRS occurred mostly during the step-up dosing phase at the lowest dose, with low rates thereafter. There were no cases of immune effector cell-associated neurotoxicity syndrome or tumor lysis syndrome.
Regulatory History and Future Studies
Odronextamab has had a complex regulatory journey. In August 2025, the FDA issued a complete response letter for a biologics license application for odronextamab to treat relapsed/refractory follicular lymphoma. Additionally, in March 2024, the agent received two CRLs for DLBCL and follicular lymphoma, based on phase 2 findings. Concerns were raised about site inspections at a plant operated by Catalent Indiana LLC.
Odronextamab is currently being investigated in several clinical trials across various disease settings, both as monotherapy and in combination regimens. These include the phase 3 OLYMPIA-2 study for follicular lymphoma and the phase 3 OLYMPIA-5 study evaluating odronextamab plus lenalidomide for follicular lymphoma.
And this is the part most people miss... The potential of odronextamab in combination with CHOP for previously untreated DLBCL patients is a significant development. However, the safety profile, particularly the management of infections and CRS, will be crucial to monitor as the study progresses. What are your thoughts on the potential of this combination therapy? Do you think it could become a new standard of care for DLBCL treatment? Share your insights in the comments below!
