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

The FDA has issued complete response letters (CRLs) to the biologics license application (BLA) for odronextamab, an investigational CD20xCD3 bispecific antibody, for patients with relapsed/refractory (R/R) follicular lymphoma and R/R diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy, according to a news release from Regeneron Pharmaceuticals.¹ Odronextamab is designed to bridge CD20 on cancer cells with CD3-expressing T cells to foster local T-cell activation and the killing of cancer cells.

The BLA for odronextamab in R/R follicular lymphoma and R/R DLBCL—the 2 most common non-Hodgkin lymphoma subtypes—was accepted for FDA priority review in September 2023.² According to Regeneron, the only approvability issue identified in the CRLs was related to enrollment status in the confirmatory trials, not issues with the clinical efficacy or safety, trial design, labeling, or manufacturing of odronextamab.¹

FDA logo on paper | Image credit: Araki Illustrations - stock.adobe.com

“Regeneron has been actively enrolling patients in multiple phase 3 trials for odronextamab as part of the OLYMPIA program—one of the largest clinical programs in lymphoma. As the OLYMPIA program is intended to change the treatment paradigm of several B-cell non-Hodgkin lymphoma subtypes—including in earlier lines of therapy—in agreeing to the program, the FDA required that the trials include both dose-finding and confirmatory portions,” the press release stated.¹ “Enrollment in the dose-finding portion has begun, but the CRLs indicate that the confirmatory portions of these trials should be underway and that the timelines to completion be agreed prior to resubmission.”

The BLA was supported by data from the phase 1 EML-1 trial (NCT02290951) and pivotal phase 2 ELM-2 trial (NCT03888105).² Data from the ELM-1 and ELM-2 trials were last presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.

In the ELM-2 trial, a cohort of 130 patients with R/R DLBCL naïve to chimeric antigen receptor (CAR) T-cell therapy who were treated with odronextamab showed a 49% objective response rate (ORR) and a 31% complete response (CR) rate at a median 21 months of follow-up, according to data presented at ASH.³ The median duration of CR was 18 months (95% CI, 10-not evaluable [NE]). In 31 patients in a dose-expansion cohort of a phase 1 trial who had received prior CAR T-cell therapy, the ORR was 48%, with 32% experiencing a CR. The median duration of CR was not reached.

Regarding safety among 140 patients in the phase 2 cohort, 99% experienced adverse events (AEs), and 79% were grade 3 or higher. The most common AEs occurring in at least 20% of patients were cytokine release syndrome (CRS; 55%), anemia (42%), pyrexia (39%), neutropenia (28%) and hypokalemia (20%), and discontinuations due to AEs occurred among 10% of patients. Additionally, there were 3 deaths due to pneumonia, 1 due to COVID-19, and 1 due to pseudomonal sepsis where the relationship to odronextamab treatment could not be excluded. Most cases of CRS were grade 1, all resolving in a median of 2 days (range, 1-133). No grade 4 or 5 CRS cases occurred.

In R/R follicular lymphoma, efficacy data from 121 patients in a phase 2 cohort, all of whom had received at least 2 prior lines of therapy, were presented at ASH.⁴ At a median follow-up of 22 months, the ORR was 82%, with 75% of patients experiencing a CR. The median duration of CR was 20.5 months (95% CI, 17-NE). Median progression-free survival was 20 months (95% CI, 15-NE), and median overall survival was not reached.

AEs occurred in all 131 patients assessed for safety, and 78% were grade 3 or higher. The most common AEs occurring in at least 20% of patients were CRS (56.5%), neutropenia (40%), pyrexia (31%), anemia (30%), infusion-related reaction (29%), arthralgia (21%), diarrhea (21%) and thrombocytopenia (20%). Most cases of CRS (68%) were grade 1, with all resolving in a median of 2 days (range, 1-51), and there were no cases of grade 4 or 5 CRS. Treatment discontinuation occurred due to AEs in 11.5% of patients. Three deaths due to pneumonia, progressive multifocal leukoencephalopathy, and systemic mycosis occurred where the relationship to treatment could not be excluded.

Odronextamab is also under review by the European Medicines Agency for the treatment of R/R follicular lymphoma and DLBCL, with the agent granted orphan drug designation in the European Union.¹

References

1. Regeneron provides update on biologics license application for odronextamab. News release. Regeneron. March 25, 2024. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/regeneron-provides-update-biologics-license-application

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. September 29, 2023. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-treatment-relapsedrefractory-follicular

3. Pivotal odronextamab (CD20xCD3) phase 2 data in patients with relapsed/refractory diffuse large B-cell lymphoma debut at ASH. News release. Regeneron Pharmaceuticals. December 11, 2022. Accessed March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/pivotal-odronextamab-cd20xcd3-phase-2-data-patients

4. Odronextamab (CD20xCED3) demonstrates high and durable complete response rate among patients with relapsed/refractory follicular lymphoma in pivotal phase 2 trial. News release. Regeneron Pharmaceuticals. December 12, 2022. Accessed September 29, 2023. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-cd20xcd3-demonstrates-high-and-durable-complete