EMA Accepts Marketing Application for Odronextamab in R/R DLBCL or Follicular Lymphoma

The European Medicines Agency (EMA) has accepted a marketing authorization application seeking the approval of odronextamab for the treatment of adult patients with relapsed/refractory (R/R) follicular lymphoma or R/R diffuse large B-cell lymphoma (DLBCL) who have progressed after at least 2 prior systemic therapies.¹

The application is supported by data from the phase 1 ELM-1 trial (NCT02290951) and the pivotal phase 2 ELM-2 trial (NCT03888105).

Data presented at the 2022 ASH Annual Meeting showed that patients with relapsed/refractory DLBCL enrolled in a phase 2 cohort 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% at a median follow-up of 21 months (range, 3-30). The median duration of CR was 18 months (95% CI, 10-not evaluable [NE]).²

In patients who were exposed to prior CAR T-cell therapy treated in a phase 1 dose-expansion cohort (n = 31), the ORR was 48% with a CR rate of 32%. The median duration of CR was not reached (NR; 95% CI, 2-NE).

Regarding safety, any-grade adverse events (AEs) were reported in 99% of evaluable patients in the phase 2 cohort (n = 140), and 79% experienced grade 3 or higher AEs. The most common any-grade AEs reported in at least 20% of patients included cytokine release syndrome (CRS; 55%), anemia (42%), pyrexia (39%), neutropenia (28%) and hypokalemia (20%).

Ten percent of patients discontinued treatment due to AEs. AEs led to 5 deaths, owing to pneumonia (n = 3), COVID-19 (n = 1) and pseudomonal sepsis (n = 1), and the relationship of odronextamab to these AEs could not be excluded.

Regarding CRS, 64% of events were grade 1, and all instances of CRS resolved. The median time to CRS resolution was 2 days (range, 1-133). No grade 4 or 5 CRS was reported, and instances of grade 2 or higher CRS were reduced with the modified step-up regimen compared with the original regimen. Among 67 patients treated with the original regimen, the rates of grade 2 and 3 CRS were 18% and 7.5%, respectively. Among the 73 patients treated with the step-up regimen, those rates were 14% and 1%, respectively.

In a relapsed/refractory follicular lymphoma cohort from ELM-2 (n = 121), patients achieved an ORR of 82% with a CR rate of 75% at a median follow-up of 22 months (range, 3-33).³ The median duration of CR was 20.5 months (95% CI, 17-NE). The median progression-free survival (PFS) and overall survival (OS) were 20 months (95% CI, 15-NE) and NR (95% CI, NE-NE), respectively.

Safety findings from this cohort showed that all patients (n = 131) experienced any-grade AEs, and grade 3 or higher AEs occurred in 78% of patients. The most common AEs reported in at least 20% of patients included CRS (56.5%), neutropenia (40%), pyrexia (31%), anemia (30%), infusion-related reaction (29%), arthralgia (21%), diarrhea (21%) and thrombocytopenia (20%). Additionally, AEs led to treatment discontinuation in 11.5% of patients. Three deaths were reported due to pneumonia, progressive multifocal leukoencephalopathy, and systemic mycosis, and odronextamab was possibly related to these events.

Sixty-eight percent of CRS events were grade 1, and all resolved at a median duration of 2 days (range, 1-51). No grade 4 or 5 CRS was reported. Patients treated with the step-up regimen (n = 63) experienced rates of grade 2 and 3 CRS of 11% and 2%, respectively. The rates of grade 2 and 3 CRS in patients treated with the original regimen (n = 68) were 18% and 6%, respectively.

ELM-2 is an ongoing, open-label, multicenter, phase 2 trial investigating odronextamab in more than 500 patients in 5 independent, disease-specific cohorts, including DLBCL, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and other subtypes of B-cell non-Hodgkin lymphoma. Patients in the follicular lymphoma cohort are required to have central histopathologic confirmation of the grade 1 to 3A disease. In other disease-specific cohorts, patients need to have disease that has relapsed after or is refractory to at least 2 prior lines of systemic therapy.⁴

The primary end point is ORR per Lugano Classification. Secondary end points include CR rate, investigator-assessed ORR, PFS, OS, duration of response (DOR), disease-control rate, safety, and quality of life.¹

The open-label, multicenter, phase 1 ELM-1 trial examined the safety and tolerability of odronextamab in patients with CD20-positive B-cell malignancies previously treated with CD20-directed antibody therapy. Patients with grade 1 to 3A follicular lymphoma and DLBCL were required to have received at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent.⁵

The primary end points were safety, dose-limiting toxicities, and ORR. Secondary end points consisted of pharmacokinetics, anti-drug antibodies, PFS, OS, DOR, and duration of CR.

References

1. Odronextamab receives EMA filing acceptance for treatment of relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. News release. Regeneron Pharmaceuticals. August 17, 2023. Accessed August 17, 2023. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-receives-ema-filing-acceptance-treatment
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 August 17, 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 August 17, 2023. https://investor.regeneron.com/news-releases/news-release-details/odronextamab-cd20xcd3-demonstrates-high-and-durable-complete
4. 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). ClinicalTrials.gov. Updated April 20, 2023. Accessed August 17, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03888105
5. Study to investigate the safety and tolerability of odronextamab in patients with CD20+ B-cell malignancies (ELM-1). ClinicalTrials.gov. Updated June 6, 2023. Accessed August 17, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT02290951