FDA Issues CRL for Odronextamab in Relapsed/Refractory Follicular Lymphoma

The FDA has issued a complete response letter (CRL) to the biologics license application (BLA) seeking the approval of odronextamab (Ordspono) for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior lines of systemic therapy.¹

In an news release from Regeneron, developer of the CD20 x CD3 bispecific antibody, it was noted that the CRL was related to observations from an FDA general site inspection at Catalent Indiana, LLC.2

This marks the second CRL issued by the FDA for odronextamab following an initial letter in March 2024, which was related to the status of confirmatory trial enrollment and not to issues of safety, efficacy, or manufacturing.2 In February 2025, the FDA accepted a resubmission of the biologics license application seeking the approval of odronextamab for the treatment of patients with relapsed/refractory FL.3

The BLA was supported by data from the phase 2 ELM-2 (NCT03888105) and phase 1 ELM-1 (NCT02290951) trials.

Notably, the confirmatory phase 3 OLYMPIA-1 trial (NCT06091254) is ongoing.

In August 2024, odronextamab received regulatory approval in the European Union for the treatment of patients with relapsed/refractory FL or relapsed/refractory diffuse large B-cell lymphoma following at least 2 prior lines of systemic therapy.4

Odronextamab is an off-the-shelf, CD20 × CD3-directed bispecific antibody designed to redirect T cells to kill malignant B cells.3

ELM-2 Trial Design and Results

The multicenter, open-label ELM-2 study enrolled 128 adult patients with grade 1 to 3a FL who were relapsed or refractory to 2 or more prior therapies, including an anti-CD20 antibody and alkylating agent.5 Patients needed to be ineligible for treatment with rituximab (Rituxan)/lenalidomide (Revlimid), and have an ECOG performance status of 0 or 1. Patients were treated with intravenous odronextamab using a step-up dosing strategy during the first cycle to mitigate cytokine release syndrome (CRS) risk.

In cycles 2 through 4, patients received 80 mg of odronextamab on days 1, 8, and 15 every 21 days. Maintenance dosing at 160 mg every 2 weeks continued until disease progression or other protocol-defined discontinuation.

The median time to first complete response (CR) was 2.6 months (IQR, 2.5-2.9), and the estimated median duration of response was 15.8 months (95% CI, 6.4-not estimable), with the longest ongoing CR reported at 53 months.

ELM-2 Safety Findings

All patients in ELM-2 experienced at least 1 treatment-emergent adverse effect (TEAE), and 92% of patients experienced treatment-related AEs (TRAEs). The most common any-grade TEAEs included CRS (56%), neutropenia (39%), and pyrexia (38%). Grade 3/4 TEAEs most commonly included neutropenia (32%), anemia (12%), and decreased neutrophil counts (12%). Most CRS events occurred during the step-up dosing phase in cycle 1 and were grade 1 or 2 in severity.

Supporting Data From ELM-1

ELM-1 evaluated odronextamab in patients with relapsed/refractory non-Hodgkin lymphoma (n = 145).6 Among efficacy-evaluable patients, the overall response rate (ORR) was 51% (95% CI, 42%-59%), with a CR rate of 37%. In a subset of patients with relapsed/refractory follicular lymphoma treated with odronextamab at doses of at least 5 mg (n = 32), the ORR was 91% (95% CI, 75%-98%), and the CR rate was 72% (95% CI, 53%-86%).

Grade 3 or higher TEAEs occurred in 82% of patients in ELM-1, with anemia (25%), lymphopenia (19%), and hypophosphatemia (19%) among the most frequently reported.

References

1. Regeneron reports second quarter 2025 financial and operating results. News release. Regeneron. August 1, 2025. Accessed August 1, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-reports-second-quarter-2025-financial-and-operating
2. Regeneron provides update on biologics license application for odronextamab. News release. Regeneron. March 25, 2024. Accessed June 9, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application
3. Odrenextamab BLA accepted for FDA review for the treatment of relapsed/refractory follicular lymphoma. News release. Regeneron. February 26, 2025. Accessed June 9, 2025. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-accepted-fda-review-treatment
4. Ordspono (odronextamab) approved in the European Union for the treatment of relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. News release. Regeneron Pharmaceuticals, Inc. August 26, 2024. Accessed August 26, 2024. https://investor.regeneron.com/news-releases/news-release-details/ordsponotm-odronextamab-approved-european-union-treatment
5. Kim TM, Taszner M, Novelli S, et al. Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma. Ann Oncol. 2024;35(11):1039-1047. doi:10.1016/j.annonc.2024.08.2239
6. Bannerji R, Arnason JE, Advani RH, et al. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Lancet Haematol. 2022;9(5):e327-e339. doi:10.1016/S2352-3026(22)00072-2