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

The FDA has issued complete response letters (CRLs) to the biologics license application (BLA) seeking the approval of odronextamab (REGN1979) for the treatment of patients with relapsed/refractory follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy.¹

According to an announcement from Regeneron—the developer of the bispecific antibody—the CRLs are related to enrollment status in confirmatory trials further evaluating the agent. Notably, the CRLs did not identify any issues regarding efficacy, safety, trial design, labeling, or manufacturing of odronextamab.

“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 company wrote in a news release. “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.”

“Regeneron is committed to working closely with the FDA and investigators to bring odronextamab to patients with relapsed/refractory follicular lymphoma and relapsed/refractory DLBCL as quickly as possible. Regeneron plans on sharing updates on enrollment and regulatory timelines later [in 2024].”

In September 2023, the FDA granted priority review to the BLA seeking the approval of odronextamab. The application was supported by data from the phase 1 ELM-1 (NCT02290951) and the pivotal phase 2 ELM-2 (NCT03888105) trials.²

At the 2022 ASH Annual Meeting, investigators presented data from ELM-2, which demonstrated that at a median follow-up of 21 months (range, 3-30), patients with relapsed/refractory DLBCL who were naive to CAR T-cell therapy (n = 130) experienced an objective response rate (ORR) of 49% and a complete response (CR) rate of 31%.The median duration of CR was 18 months (95% CI, 10–not evaluable [NE]).³

For patients with relapsed/refractory follicular lymphoma evaluable for efficacy during ELM-2 (n = 121), findings showed that at a median follow-up of 22 months (range, 3-33), odronextamab elicited an ORR of 82% and a CR rate of 75%. The median duration of CR was 20.5 months (95% CI, 17-NE), and these patients experienced a median progression-free survival (PFS) of 20 months (95% CI, 15-NE) and a median overall survival (OS) that was not yet reached (95% CI, NE-NE).⁴

Furthermore, findings from ELM-1 showed that treatment with the CD20- and CD3-directed bispecific antibody 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 = 145). Patients with relapsed/refractory DLBCL that were naive to CAR T-cell therapy (n = 49) experienced an ORR and CR rate of 39% (95% CI, 25.2%-53.8%) and 24% (95% CI, 13.3%-38.9%), respectively. Patients with relapsed/refractory DLBCL treated with prior CAR T-cell therapy (n = 33) achieved an ORR of 33% (95% CI, 18.0%-51.8%) and a CR rate of 24% (95% CI, 11.1%-42.3%).⁵

Patients with relapsed/refractory grade 1 to 3a follicular lymphoma (n = 40) attained an ORR of 78% (95% CI, 61.5%-89.2%) and a CR rate of 63% (95% CI, 45.8%-77.3%).

ELM-2

ELM-2 enrolled patients with previously treated non-Hodgkin lymphoma, and those with DLBCL needed to be relapsed/refractory to at least 2 prior lines of systemic therapy. Those included in the follicular lymphoma cohort needed to have central histopathologic confirmation of the grade 1 to 3a disease. Although patients with grade 3b follicular lymphoma were not included in this cohort, they were permitted to enroll in the other B-cell non-Hodgkin lymphoma cohort. Key inclusion criteria for all patients included measurable disease documented by diagnostic imaging; an ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function.⁶

Initially, eligible patients with relapsed/refractory DLBCL received step-up dosing consisting of 1 mg of odronextamab on days 1 and 2 of cycle 1, then 20 mg split over days 8 and 9 of cycle 1, followed by the full dose of 160 mg given weekly starting on day 15 of cycle 1.⁷ To further mitigate the risk of cytokine release syndrome (CRS), the protocol was amended to include the addition of an intermediary step-up dose. Patients received 0.7 mg split over day 1 (0.2 mg) and day 2 (0.5 mg) of cycle 1, then 4 mg split over days 8 and 9, followed by 20 mg split over days 15 and 16. The full 160-mg dose was given once per week starting on day 1 of cycle 2 and continued through the end of the fourth 21-day cycle. After cycle 4, 320 mg of odronextamab was given once every 2 weeks as maintenance until patients experienced disease progression or unacceptable toxicity.

Patients with relapsed/refractory grade 1 to 3a follicular lymphoma were administered an initial step-up regimen that included 1 mg of odronextamab split over day 1 and day 2 of cycle 2, then 20 mg split over day 8 and 9, followed by a full 80-mg dose given once per week starting on day 15.8 With the modified step-up regimen, patients were administered 0.7 mg of odronextamab split over day 1 (0.2 mg) and 2 (0.5 mg), then 4 mg split over days 8 and 9, and then 20 mg split over days 15 and 16. The full 80-mg dose was given once per week starting on day 1 of cycle 2 and continued through the end of cycle 4. Patients were then given 160 mg of odronextamab once every 2 weeks until disease progression or unacceptable toxicity.

The primary end point was ORR per independent central review. Secondary end points consisted of investigator-assessed ORR, CR rate, PFS, OS, duration of response (DOR), disease control rate, and safety.⁵

Ninety-nine percent of patients with relapsed/refractory DLBCL (n = 140) experienced any-grade adverse effects (AEs), and 79% of patients had grade 3 or higher AEs. The most common any-grade AEs were CRS (55%), anemia (42%), pyrexia (39%), neutropenia (28%) and hypokalemia (20%).³

In patients who experienced CRS, 64% of these events were grade 1 and resolved in a median of 2 days (range, 1-133). No grade 4 or 5 CRS occurred. In patients treated with the original regimen (n = 67), rates of grade 2 and grade 3 CRS were 18% and 7.5%, respectively. Those rates were 14% and 1%, respectively, for patients given the modified step-up regimen (n = 73).

AEs led to treatment discontinuation in 10% of patients. AEs led to death in 5 patients, including pneumonia (n = 3), COVID-19 (n = 1), and pseudomonal sepsis (n = 1), where the relationship to odronextamab could not be excluded.

Safety data from patients with relapsed/refractory follicular lymphoma (n = 131) showed that the rate of any-grade AEs was 100%. The rate of grade 3 or higher AEs was 78%.4 The most common any-grade AEs included CRS (56.5%), neutropenia (40%), pyrexia (31%), anemia (30%), infusion-related reaction (29%), arthralgia (21%), diarrhea (21%), and thrombocytopenia (20%).

Sixty-eight percent of instances of CRS were grade 1 and resolved in a median of 2 days (range, 1-51). No grade 4 or 5 CRS was observed. The rates of grade 2 and 3 CRS were 18% and 6%, respectively, for the original regimen (n = 68). They were 11% and 2%, respectively, with the modified step-up dosing (n = 63).

ELM-1

The single-arm, multicenter, phase 1, dose-escalation and -expansion ELM-1 study enrolled patients at least 18 years of age with CD20-positive relapsed/refractory B-cell malignancies.⁵ Patients needed to have prior treatment with a CD20-directed antibody, at least 1 measurable lesion, and an ECOG performance status of 0 or 1.

Odronextamab was given in a step-up dosing schedule in cycle 1, then once weekly at target doses ranging from 0.1 mg to 320 mg in cycles 2 to 4. After four 21-day cycles, patients received maintenance odronextamab once every 2 weeks until disease progression or unacceptable toxicity.

The primary end points were safety and the incidence of dose-limiting toxicities. ORR was a key secondary end point.

Safety data for all patients (n = 145) showed that the most common grade 3 or higher treatment-emergent AEs (TEAEs) included anemia (25%), lymphopenia (19%), hypophosphatasemia (19%), neutropenia (19%), and thrombocytopenia (14%). Serious TEAEs were reported in 61% of patients, including CRS (28%), pyrexia (8%), pneumonia (6%), and infusion-related reaction (4%).

Deaths considered related to treatment occurred in 4 patients, which included 1 instance each of gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumor-lysis syndrome.

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 (CD20xCD3) 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 March 25, 2024. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-cd20xcd3-demonstrates-high-and-durable-complete
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
6. A study to assess the anti-tumor activity and safety of odronextamab in patients with B-cell non-Hodgkin lymphoma that have been previously treated (ELM-2). ClincialTrials.gov. Updated March 19, 2024. Accessed March 25, 2024. https://classic.clinicaltrials.gov/ct2/show/study/NCT03888105
7. Kim WS, Kim TM, Cho SG, et al. Odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): results from a prespecified analysis of the pivotal phase II study ELM-2. Blood. 2022;140(suppl 1):1070-1071. doi:10.1182/blood-2022-158406
8. Kim TM, Taszner M, Cho SG, et al. Odronextamab in patients with relapsed/refractory (R/R) follicular lymphoma (FL) grade 1-3a: results from a prespecified analysis of the pivotal phase II study ELM-2. Blood. 2022;140(suppl 1):2280-2282. doi:10.1182/blood-2022-158404