FDA Grants Priority Review to Odronextamab in Relapsed/Refractory Follicular Lymphoma or DLBCL

FDA

The FDA has granted priority review to the biologics license application (BLA) seeking the approval of odronextamab (REGN1979) for the treatment of adult patients with relapsed/refractory follicular lymphoma or relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have progressed after at least 2 prior systemic therapies.¹

The BLA is supported by data from the phase 1 ELM-1 (NCT02290951) and the pivotal phase 2 ELM-2 trial (NCT03888105). The FDA has assigned a target action date of March 31, 2024, under the Prescription Drug User Fee Act.

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

At a median follow-up of 22 months (range, 3-33), patients with relapsed/refractory follicular lymphoma evaluable for efficacy during the phase 2 study (n = 121) achieved an ORR of 82% and a CR rate of 75%.³The median duration of CR was 20.5 months (95% CI, 17-NE). 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).

Findings from ELM-1 showed that all efficacy-evaluable patients with non-Hodgkin lymphoma (n = 145) experienced an ORR of 51% (95% CI, 42%-59%) and a CR rate of 37% (95% CI, 29%-45%).⁴ In patients with relapsed/refractory DLBCL who did not receive prior CAR T-cell therapy (n = 49), the ORR and CR rate was 39% (95% CI, 25.2%-53.8%) and 24% (95% CI, 13.3%-38.9%), respectively. Those with relapsed/refractory DLBCL who had 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%).

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% Cim 45.8%-77.3%).

ELM-2 Design and Safety

The open-label ELM-2 trial evaluated the antitumor activity and safety of odronextamab patients with previously treated non-Hodgkin lymphoma.⁵ All patients were required to have measurable disease documented by diagnostic imaging, an ECOG performance status of 0 or 1, and adequate bone marrow, hepatic, and renal function.

Those with DLBCL needed to be relapsed/refractory to at least 2 prior lines of systemic therapy. Patients in the follicular lymphoma cohort were required to have central histopathologic confirmation of the grade 1 to 3a disease. Those with grade 3b follicular lymphoma were not permitted in this cohort; however, they were allowed to enroll in the other B-cell non-Hodgkin lymphoma cohort.

Key exclusion criteria for all patients included primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS non-Hodgkin lymphoma; any systemic anti-lymphoma therapy within 5 half-lives or within 28 days of the first dose of odronextamab; history of allogeneic stem cell transplantation; or any prior CAR T-cell therapy.

Patients with DLBCL initially 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 1.6 The trial protocol was revised to further mitigate the risk of cytokine release syndrome (CRS) with 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 this 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.

In the follicular lymphoma cohort, the initial step-up regimen 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 a full 80-mg dose given once per week starting on day 15.7 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 weeks 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.

ORR per independent central review served as the trial’s primary end point. Secondary end points included investigator-assessed ORR, CR rate, PFS, OS, duration of response (DOR), disease control rate, and safety.⁵

Regarding safety, 99% of patients with relapsed/refractory DLBCL (n = 140) experienced any-grade adverse effects (AEs). The rate of grade 3 or higher AEs was 79%. The most common any-grade AEs included CRS (55%), anemia (42%), pyrexia (39%), neutropenia (28%) and hypokalemia (20%).2 Among patients who experienced CRS, 64% of cases were grade 1 and resolved in a median of 2 days (range, 1-133). No grade 4 or 5 CRS was reported. For 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)

Ten percent of patients discontinued treatment due to AEs. AEs led to deaths 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.

In patients with relapsed/refractory follicular lymphoma (n = 131), the rates of any-grade AEs and grade 3 or higher AEs were 100% and 78%, respectively.³ The most common any-grade AEs consisted of 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 Design and Safety

ELM-1 was a single-arm, multicenter, phase 1, dose-escalation and -expansion study that enrolled patients at least 18 years of age with CD20-positive relapsed/refractory B-cell malignancies.4 Patients were required 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 administered in step-up dosing schedule in cycle 1, then once weekly at target doses ranging from 0.1 mg to 320 mg during in cycles 2 to 4. After four 21-day cycles, patients received maintenance odronextamab once every 2 weeks until disease progression or unacceptable toxicity.

Safety and the incidence of dose-limiting toxicities served as the trial’s primary end points. ORR was a key secondary end point.

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

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

References

1. 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 September 29, 2023. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-bla-treatment-relapsedrefractory-follicular
2. 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 September 29, 2023. https://investor.regeneron.com/news-releases/news-release-details/pivotal-odronextamab-cd20xcd3-phase-2-data-patients
3. 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
4. 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
5. 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 April 20, 2023. Accessed September 29, 2023. https://classic.clinicaltrials.gov/ct2/show/study/NCT03888105
6. Kim W-S, Kim TM, Cho S-G, 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
7. Kim TM, Taszner M, Cho S-G, 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