FDA Issues CRL to Odronextamab in Pretreated Follicular Lymphoma

The complete response letter for the agent is due to observations from an FDA general site inspection at Catalent Indiana LLC.

The FDA has issued a complete response letter (CRL) for the biologics license application (BLA) for the bispecific antibody odronextamab (Ordspono) in the treatment of patients with relapsed/refractory follicular lymphoma who received 2 or more lines of systemic therapy, according to the developer, Regeneron.1

The agency accepted the BLAin February 2025 and set a Prescription Drug User Fee Act date of July 30, 2025.2 Regeneron announced that the CRL was caused by observations from an FDA general site inspection at Catalent Indiana LLC.

Results from the phase 1 ELM-1 (NCT02290951) and phase 2 ELM-2 trials (NCT03888105) provided context for the efficacy and safety of odronextamab in this patient population.

ELM-2

The phase 2 ELM-2 trial evaluated the anti-tumor activity and safety of odronextamab in patients with relapsed/refractory follicular lymphoma and B-cell non-Hodgkin Lymphoma. Updated results from the trial were shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.3

With a median follow-up of 28.3 months (95% CI, 25.5-32.8), the objective response rate (ORR) was 80.5% (95% CI, 72.5%-86.9%), with a complete response (CR) rate of 74.2% (95% CI, 65.7%-81.5%). It was noted that the ORR was consistent across most high-risk subgroups.

The median duration of response (DOR) was 26.0 months (95% CI, 18.8-42.5), with a 24-month DOR rate of 52.0% (95% CI, 40.9%-62.0%) and a 36-month DOR rate of 42.1% (95% CI, 29.6%-54.1%). The median duration of complete response was 32.2 months (95% CI, 20.8-42.6), with a 24-month rate of 56.3% (95% CI, 44.6%-66.4%) and a 36-month rate of 45.6% (95% CI, 32.2%-58.1%).

In all patients, the median progression-free survival (PFS) was 23.0 months (95% CI, 17.7-29.0), with a 24-month PFS rate of 49.8% (95% CI, 40.1%-58.7%) and a 36-month PFS rate of 37.5% (95% CI, 27.2%-47.8%). The median overall survival (OS) was 54.2 months (95% CI, 40.4-not evaluable [NE]), with 24- and 36-month OS rates of 70.9% (95% CI, 61.7%-78.3%) and 62.6% (95% CI, 52.1%-71.5%).

In patients who achieved CRs, the median PFS was 34.5 months (95% CI, 24.6-45.5), with 24- and 36-month PFS rates of 62.8% (95% CI, 51.6%-72.2%) and 48.8% (95% CI, 35.9%-60.6%). The median OS was 54.2 months (95% CI, 54.2-NE), with 24- and 36-month OS rates of 81.1% (95% CI, 71.3%-87.8%) and 73.2% (95% CI, 61.0%-82.1%).

In those who achieved PRs, the median PFS was 9.9 months (95% CI, 4.4-17.2), with a 24- and 36-month PFS rate of 0 (95% CI, NE-NE) for both. The median OS was 18.4 months (95% CI, 12.6-NE), with 24- and 36-month OS rates of 17.9% (95% CI, 0.8%-53.8%) and NE (95% CI, NE-NE).

Additionally, the median PFS in those with a high CAR-HEMATOTOX score (n = 16) was 23.0 months (95% CI, 8.5-45.5) vs 24.1 months (95% CI, 17.7-38.0) in those with a low score (n = 102). The median OS in those with a high score was 27.5 months (95% CI, 12.8-NE) vs 54.2 months (95% CI, 43.7-NE) in those with a low score.

The median PFS in patients with circulating tumor DNA (ctDNA) detected by 12 weeks was 21.6 months (95% CI, 5.9-32.1) vs 42.4 months (95% CI, 35.2-NE) in those without ctDNA detected (HR, 0.31; 95% CI, 0.14-0.67).

The trial enrolled patients 18 years or older with grade 1 to 3a follicular lymphoma who are relapsed/refractory after at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent, and have an ECOG performance status of 0 or 1.

Patients received odronextamab intravenously; in cycle 1, patients received it at 0.7 mg on days 1 and 2, 4 mg on days 8 and 9, and 20 mg on days 15 and 16, and in cycles 2 to 4, patients received it at 80 mg on days 1, 8, and 15. In the maintenance period, patients received 160 mg every 4 weeks if they had a CR for at least 9 months.

The trial’s primary end point was ORR per independent review committee. Secondary end points included ORR per local investigator, DOR, PFS, OS, safety and tolerability, and patient-reported outcomes.

Regarding safety, the most common treatment-emergent adverse effects (TEAEs) of any grade were cytokine release syndrome (CRS; 56.2%), neutropenia (39.8%), pyrexia (38.2%), and anemia (34.4%). TEAEs led to treatment discontinuation in 18.8% of patients.

Infections were reported in 79.7% of all patients, with infections of grade 3, 4, and 5 occurring in 28.1%, 3.1%, and 12.5%.

The median time to CRS onset was 19.67 hours (range, 0.7-159.0), with a median CRS duration of 7.72 hours (range, 0.6-184.0); management for CRS was systemic steroids (33.3%), tocilizumab (Actemra; 16.7%), and both (15.0%).

ELM-1

The phase 1 ELM-1 trial evaluated the safety and tolerability of odronextamab in patients with CD20-positive B-cell malignancies that were previously treated with a CD-20–directed antibody therapy.4

In part B of the trial, patients had grade 1 to 3a follicular lymphoma and received at least 2 prior lines of systemic therapy. Additional enrollment criteria include an ECOG performance status of 0 or 1, a life expectancy of at least 6 months, and adequate bone marrow and organ function.

The primary end point was safety and the overall frequency of AEs. Secondary end points were ORR, pharmacokinetics, OS, PFS, DOR, and DOCR.

References

1. Regeneron reports second quarter 2025 financial and operating results. News release. Regeneron. August 1, 2025. Accessed August 1, 2025. https://tinyurl.com/srxef2u6
2. Odronextamab BLA accepted for FDA Review for the treatment of relapsed/refractory follicular lymphoma. News release. Regeneron Pharmaceuticals, Inc. February 26, 2025. Accessed August 4, 2025. https://tinyurl.com/nhzwz4hv
3. Jagadeesh D, Taszner M, Chong G, et al. Long-term follow-up of the phase 2 ELM-2 study: Odronextamab for patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). J Clin Oncol. 2025;43(suppl_16):2049. doi:10.1200/JCO.2025.43.16_suppl.7049
4. Study to investigate the safety and tolerability of odronextamab in patients with CD20+ B-cell malignancies (ELM-1). ClinicalTrials.gov. Updated November 5, 2024. Accessed August 4, 2025. https://tinyurl.com/2kxan74f