FDA Accepts Resubmission of BLA for Odronextamab in R/R Follicular Lymphoma

The FDA has accepted a resubmission of the biologics license application (BLA) seeking approval of odronextamab (Ordspono) for the treatment of patients with relapsed/refractory follicular lymphoma after 2 or more lines of systemic therapy.¹

The acceptance of the BLA resubmission followed a complete response letter (CRL) issued by the FDA in March 2024.² The CRLs were related to the enrollment status in confirmatory trials and did not establish any issues regarding efficacy, safety, trial design, or manufacturing of odronextamab, according to Regeneron Pharmaceuticals, the developer of the agent.

The FDA set a new Prescription Drug User Fee Act (PDUFA) date of July 30, 2025, for odronextamab.¹

The BLA resubmission and acceptance from the FDA followed the achievement of the phase 3 confirmatory OLYMPIA-1 trial (NCT06091254) for patients with relapsed/refractory follicular lymphoma. However, data from the phase 1 ELM-1 (NCT02290951) and phase 2 ELM-2 (NCT03888105) trials supported the BLA resubmission, which demonstrated an overall response rate (ORR) of 80% (n = 103), with 74% (n = 95) achieving complete responses (CRs). Serious adverse effects (AEs) occurred in 67% of patients and included cytokine release syndrome (CRS), COVID-19, and pneumonia in at least 10%.

In August 2024, the European Commission approved odronextamab for the treatment of adult patients with relapsed/refractory follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma who previously received at least 2 lines of systemic therapy.³ The regulatory decision was based on data from the phase 1 ELM-1 and phase 2 ELM-2 trials.

At a data cutoff of October 20, 2023, in the ELM-2 study, median duration of efficacy follow-up was 20.1 months among patients with relapsed/refractory follicular lymphoma.⁴ The ORR by independent central review was 80% (95% CI, 72.5%-86.9%; n = 103/128), with a CR rate of 73% in more than 90% of responders. ORR and CR rates per local investigators were 82% and 73%, respectively. In 95% of all evaluable patients, a reduction in tumor size was recorded.

Findings from the ELM-1 study demonstrated that treatment of odronextamab led to an ORR of 51% (95% CI, 42%-59%) and a CR rate of 37% (95% CI, 29%-45%) in efficacy-evaluable patients with non-Hodgkin lymphoma (n = 142).⁵ Notably, patients with relapsed/refractory follicular lymphoma who were treated with odronextamab at 5 mg or greater (n = 32) had an ORR of 91% (95% CI, 75%-98%), and a CR rate of 72% (95% CI, 53%-86%). The estimated median duration of response was 15.8 months (95% CI, 6.4–not estimable), with the longest ongoing CR of 53.0 months; responses occurred early with a median time to first CR of 2.6 months (IQR, 2.5-2.9).

ELM-2 Study

In the follicular lymphoma cohort (n = 128), patients were at least 18 years of age, had grade 1 to 3a follicular lymphoma with central histopathologic confirmation, were refractory to or had relapsed on 2 or more prior lines of systemic therapy, which included an anti-CD20 antibody and alkylator, were not considered for treatment with rituximab (Rituxan)/lenalidomide (Lenvima), and had an ECOG performance status of 0 or 1.⁴

Patients were treated with intravenous (IV) odronextamab in 21-day cycles, of which step-up dosing was implemented in cycle 1 to mitigate risks of CRS and was followed by odronextamab at 80 mg on days 1, 8, and 15 in cycles 2 to 4. Maintenance dosing continued with odronextamab at 160 mg every 2 weeks until disease progression or treatment discontinuation based on another protocol-defined reason.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) occurred in all patients, with 92% of patients experiencing at least 1 treatment-related AE (TRAE). The most common TEAEs of any grade included CRS (56%), neutropenia (39%), and pyrexia (38%); most common grade 3/4 TEAEs included neutropenia (32%), anemia (12%), and decreased neutrophil levels (12%).

ELM-1 Study

Patients included in the study (n = 145) had documented B-cell non-Hodgkin lymphoma defined by 2007 NCI working group criteria, at least 1 measurable lesion of at least 1.5 cm on the longest diameter, at least 1 previous treatment with anti-CD20 antibody, an ECOG performance status of 0 or 1, and adequate hematological and organ function.⁵

Patients were treated with IV odronextamab in 21-day cycles, based on a step-up dose in cycle 1, then treatment once per week at doses ranging from 0.1 mg to 320 mg on days 1, 8, and 15 during cycles 2 to 4. Following cycle 4, maintenance therapy was administered every 2 weeks until disease progression or unacceptable toxicity.

All patients experienced at least 1 TEAE of any grade and 93% of patients had at least 1 TRAE. Grade 3 or greater TEAEs occurred in 82% of patients, which included anemia (25%), lymphopenia (19%), hypophosphatemia (19%), neutropenia (19%), and thrombocytopenia (14%). Of note, most CRS events were grades 1 or 2 (36% and 19%, respectively), and mainly occurred in cycle 1 of treatment during step-up dosing.

References

1. Odrenextamab BLA accepted for FDA review for the treatment of relapsed/refractory follicular lymphoma. News Release. Regeneron. February 26, 2025. Accessed February 26, 2025. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-accepted-fda-review-treatment
2. Regeneron provides update on biologics license application for odronextamab. News Release. Regeneron. March 25, 2024. Accessed February 26, 2025. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application
3. 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. August 26, 2024. Accessed February 26, 2025. https://investor.regeneron.com/news-releases/news-release-details/ordsponotm-odronextamab-approved-european-union-treatment
4. 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
5. 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