FDA Issues CRLs for Odronextamab in R/R Follicular Lymphoma and DLBCL

The FDA previously granted priority review to odronextamab in relapsed/refractory follicular lymphoma and relapsed/refractory DLBCL in September 2023.

The FDA has issued 2 complete response letters (CRLs) for a biologics license application (BLA) seeking approval of odronextamab as a treatment for patients with relapsed/refractory follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) following 2 or more prior lines of systemic therapy, according to a press release from Regeneron Pharmaceuticals, the developers of the agent.¹

The regulatory agency highlighted issues associated with the enrollment status of confirmatory trials in the aforementioned populations. There were no problems related to the efficacy or safety of odronextamab, the trial designs, or the manufacturing and labelling of the agent.

Developers initiated patient enrollment across multiple phase 3 studies in its OLYMPIA program. The FDA required that these trials include both dose-finding and confirmatory portions. Enrollment for the dose-finding phases is underway, and the confirmatory portions are expected to begin as well; the FDA will agree upon a completion timeline with developers before applications are resubmitted.

The FDA previously granted priority review to odronextamab in relapsed/refractory follicular lymphoma and relapsed/refractory DLBCL in September 2023.² Data from the phase 1 ELM-1 trial (NCT02290951) and the phase 2 ELM-2 trial (NCT03888105) supported the BLA. Investigators presented updated findings from both trials at the 2023 American Society of Hematology (ASH) Annual Meeting.

ELM-2 Trial

With a minimum follow-up of 36 weeks among 127 patients with DLBCL, data from the ELM-2 trial highlighted an objective response rate (ORR) of 52% and a complete response (CR) rate of 31%.³ Investigators reported responses across various high-risk subgroups, including patients with double-hit and triple-hit high-grade lymphoma as well as those with transformed DLBCL. Additionally, the median duration of response (DOR) with odronextamab was 10 months (95% CI, 5-18), and the median duration of CR was 18 months (95% CI, 10-not estimable [NE]).

In the phase 2 trial, common adverse effects (AEs) included cytokine release syndrome (CRS; 55%), pyrexia (43%), anemia (39%), and neutropenia (31%). Investigators reported CRS in 53% of patients who were treated with the recommended step-up regimen (n = 60). There were no instances of immune effector cell-associated neurotoxicity syndrome (ICANS) in the trial.

Investigators of the open-label ELM-2 trial evaluated treatment with odronextamab in 375 patients, which included those with DLBCL, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and other B-cell non-Hodgkin lymphoma subtypes.

The primary end point was ORR based on Lugano criteria. Secondary end points included CR, progression-free survival (PFS), overall survival, DOR, disease control rate, safety, and quality of life.

ELM-1 Trial

Among 44 evaluable patients, including 73% who were refractory to CAR T-cell therapy, the ORR was 48% based on independent central review, and the CR rate was 30%. Data highlighted that 8 patients with a partial response converted to a CR during the study period. Additionally, the median DOR was not reached (95% CI, 2-NE) after a median follow-up of 5 months (95% CI, 3-9).

Common AEs in the trial included CRS (52%), anemia (34%), pyrexia (34%), and fatigue (34%). Specifically, grade 1 CRS affected 27% (n = 12) of patients, and grade 2 events occurred in 25% (n = 11).

Investigators of the open-label phase 1 ELM-1 trial assessed the tolerability and safety of odronextamab in patients with CD20-positive B-cell malignancies who received prior treatment with anti-CD20 therapy. The study included an expansion cohort in which investigators evaluated those with DLBCL who had disease progression following prior CAR T-cell therapy.

References

1. Regeneron provides update on biologics license application for odronextamab. News release. Regeneron Pharmaceuticals, Inc. March 25, 2024. Accessed March 26, 2024. https://tinyurl.com/uwtm4fxb
2. Odronextamab BLA for treatment of relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) accepted for FDA priority review. News release. Regeneron Pharmaceuticals, Inc. September 29, 2023. Accessed March 26, 2024. https://bit.ly/3ZzBuJm
3. Updated odronextamab data from relapsed/refractory diffuse large B-cell lymphoma pivotal trial showed deep and durable responses and the potential of ctDNA to predict long-term outcomes. News release. Regeneron Pharmaceuticals, Inc. December 10, 2023. Accessed March 26, 2024. https://tinyurl.com/bdf4dwe9