EMA Accepts Marketing Application for Odronextamab in R/R DLBCL, Follicular Lymphoma


The European Medicines Agency (EMA) has accepted a Marketing Authorization Application (MAA) for odronextamab for relapsed/refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL) following disease progression after at least 2 prior lines of systemic therapy.

The European Medicines Agency (EMA) has accepted for review the Marketing Authorization Application (MAA) for odronextamab, an investigational bispecific antibody manufactured by Regeneron Pharmaceuticals, for the treatment of adult patients with relapsed/refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL) who have progressed after at least 2 prior lines of systemic therapy, the company announced in a press release.1

Odronextamab, a CD20 x CD3 bispecific antibody, is designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer cell killing. The agent was previously granted Orphan Drug Designation by the EMA for FL and DLBCL,1 which are the most common subtypes of B-cell non-Hodgkin lymphoma (B-NHL).2 While FL is considered indolent, DLBCL is an aggressive subtype of NHL.

The investigational drug has potential to fill a need for patients whose hematological cancers progress because these patients often experience disease progression following first-line treatment, and these cancer types become increasingly difficult to treat upon progression, according to the release. There are few effective treatment options in the third line or later for these cancers.

Data from the phase 1 ELM-1 trial (NCT02290951) and pivotal phase 2 ELM-2 trial (NCT03888105) support the MAA. The ongoing ELM-1 trial is an open-label, multicenter phase 1 trial investigating odronextamab’s safety and tolerability in patients with CD20-positive B-cell malignancies who have previously undergone treatment with CD20-directed antibody therapy.3 In ELM-2, the main outcome of interest is the anti-tumor activity of odronextamab monotherapy administered intravenously in 5 disease-specific cohorts: FL, DLBCL, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and a cohort comprising patients with other B-NHLs.4

Pivotal Data Presented at ASH 2022

Pivotal data supporting the MAA were presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition, including efficacy data from a cohort of 130 chimeric antigen receptor (CAR) T-cell therapy­–naïve patients with R/R DLBCL in the ELM-2 study and 31 CAR-T experienced patients in a dose expansion cohort of the ELM-1 trial.5 All patients had received at least 2 prior lines of therapy, including a CD20 antibody and an alkylating agent.

In patients who were naïve to CAR T-cell therapy, the objective response rate (ORR) at a median follow-up of 21 months (range, 3-30) was 49%, and 31% of responders achieved a complete response (CR). The median CR duration was 18 months (95% CI, 10-not evaluable [NE]) in the CAR T-cell therapy­–naïve cohort. Among patients who received CAR T-cell therapy prior to odronextamab, the ORR was 48% at a median follow-up of 24 months (range, 3-38.5), 32% of whom experienced CR. The median duration of CR was not reached (95% CI, 2 months to NE).

Safety was assessed in 140 patients in the phase 2 cohort, and 99% of those patients experienced adverse events (AEs), 79% of which were grade 3 or higher. The most common AEs were CRS, anemia, pyrexia, neutropenia, and hypokalemia, which occurred in 55%, 42%, 39%, 28%, and 20% of patients, respectively. Ten percent of patients discontinued treatment due to AEs. Five deaths occurred where the relationship to treatment could not be excluded, with 3 due to pneumonia, 1 due to COVID-19, and 1 attributed to pseudomonal sepsis.

Also at ASH 2022, efficacy data from 121 patients with R/R FL enrolled in the phase 2 trial were presented.6 At a median follow-up of 22 months (range, 3-33 months), the ORR was 82%, 75% of whom experienced CR. The median duration of CR was 20.5 months (95% CI, 17-NE), and the median progression-free survival was 20 months (95% CI, 15-NE). The median OS was not reached at the time of the presentation.

The most common AEs in the R/R FL cohort were CRS (56.5%), neutropenia (40%), pyrexia (31%), anemia (30%), infusion-related reaction (29%), arthralgia (21%), diarrhea (21%) and thrombocytopenia (20%). AEs led to discontinuation in 11.5% of patients, and 3 deaths occurred due to pneumonia, progressive multifocal leukoencephalopathy, and systemic mycosis that could not exclude treatment as a contributor.

In both the FL and DLBCL analyses, CRS was the most common AE, with the majority of cases being grade 1. All CRS cases resolved, and none of grade 4 or 5 were reported in either cohort.

With both the ELM-1 and ELM-2 trials still ongoing, a broad phase 3 development program is underway to investigate odronextamab in earlier lines of therapy and in more types of B-NHL. The program is one of the largest clinical programs in lymphoma, according to the press release.1 Odronextamab was previously granted Fast Track Designation for FL by the FDA,6 but the safety and efficacy of the investigational agent have not been fully evaluated by regulatory authorities.


1.Odronextamab receives EMA filing acceptance for treatment of relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. News release. Regeneron. August 17, 2023. Accessed August 18, 2023. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-receives-ema-filing-acceptance-treatment

2. NHL subtypes. Leukemia & Lymphoma Society. Accessed August 18, 2023. https://www.lls.org/lymphoma/non-hodgkin-lymphoma/nhl-subtypes

3. Study to investigate the safety and tolerability of odronextamab in patients with CD20+ B-cell malignancies (ELM-1). ClinicalTrials.gov. Updated June 6, 2023. Accessed August 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02290951

4. A study to assess the anti-tumor activity and safety of odronextamab in patients with B-cell non-Hodgkin lymphoma that have been previously treated (ELM-2). ClinicalTrials.gov. Updated April 20, 2023. Accessed August 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03888105

5. Pivotal odronextamab (CD20xCD3) phase 2 data in patients with relapsed/refractory diffuse large B-cell lymphoma debut at ASH. News release. Regeneron. December 11, 2022. Accessed August 18, 2023.


6. Odronextamab (CD20xCD3) demonstrates high and durable complete response rate among patients with relapsed/refractory follicular lymphoma in pivotal phase 2 trial. News release. Regeneron. December 12, 2022. Accessed August 18, 2023. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-cd20xcd3-demonstrates-high-and-durable-complete

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