Regeneron Pharmaceuticals announced updated data on odronextamab, an investigational CD20xCD3 bispecific antibody, in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The data, presented at the 65th American Society of Hematology (ASH) Annual Meeting, highlight the potential of odronextamab as a promising treatment option for this aggressive blood cancer. The pivotal Phase 2 trial (ELM-2) and Phase 1 trial (ELM-1) results demonstrated deep and durable responses, even in patients who had progressed on CAR-T therapy.
Phase 2 Trial Results
The primary analysis of the Phase 2 ELM-2 trial, involving 127 DLBCL patients, showed a 52% objective response rate (ORR) with 31% achieving a complete response (CR). These responses were observed across high-risk subgroups, including those with International Prognosis Index (IPI) high-risk scores of 3 to 5, high-grade lymphoma that is double-hit and triple-hit, and transformed DLBCL. The median duration of response (DoR) was 10 months (95% CI: 5 to 18 months), with a 30-month median duration of follow-up for efficacy evaluable patients (95% CI: 20 to 33 months). The median duration of CR was 18 months (95% CI: 10 months to not estimable).
Sabarish Ram Ayyappan, M.D., medical director of hematologic malignancies, City of Hope Atlanta, and a trial investigator, stated, "The primary analysis from the pivotal trial of odronextamab demonstrated impressive response rates, including in certain high-risk subgroups. Furthermore, these responses were durable and consistent with those seen in a Phase 1 trial in patients who had previously progressed on CAR-T therapy, a population with a very poor prognosis."
Phase 1 Trial in CAR-T Progressed Patients
An additional analysis from the Phase 1 trial demonstrated encouraging and durable antitumor activity with odronextamab in heavily pretreated patients who had progressed after CAR-T therapy. Among 44 efficacy-evaluable patients, including 73% who were CAR-T refractory, the ORR was 48%, with 30% achieving a CR. Notably, 8 patients converted from a partial response to a CR over the study period. Both median DoR and median duration of CR were not reached (95% CI: 2 to NE) with a 5-month median duration of follow-up (95% CI: 3 to 9 months).
ctDNA Analysis and Progression-Free Survival
In a separate oral presentation on an exploratory analysis from the Phase 2 trial, data showed a positive association between minimal residual disease (MRD) status, as measured by circulating tumor DNA (ctDNA), and progression-free survival (PFS). Among 70 R/R DLBCL and 65 R/R follicular lymphoma (FL) patients assessed, nearly all were MRD-positive at baseline. Notably, those who were MRD-negative at the time of the first response assessment (Cycle 4, Day 15) had significantly longer PFS than those who remained MRD-positive (DLBCL Hazard Ratio [HR]: 0.27, 95% CI: 0.12 to 0.61; FL HR: 0.26, 95% CI: 0.1 to 0.66).
Jon E. Arnason, M.D., hematologist and oncologist, Beth Israel Deaconess Medical Center, and a trial investigator, commented, "These findings strengthen the body of evidence supporting the importance of minimal residual disease status as a monitoring tool in the course of managing patients with lymphoma. As the data for circulating tumor DNA continues to grow, these insights may help inform future response-directed treatment paradigms."
Regulatory Status
Odronextamab is currently under regulatory review for the treatment of R/R DLBCL and R/R FL by the U.S. Food and Drug Administration (FDA), with a target action date of March 31, 2024, as well as by the European Medicines Agency (EMA). In the U.S., odronextamab has been granted Fast Track Designation for DLBCL and FL by the FDA. In the European Union, odronextamab has been granted Orphan Drug Designation in DLBCL and FL by the EMA.
Safety Profile
The most common adverse events (AE) in ≥30% patients were cytokine release syndrome (CRS; 55%), pyrexia (43%), anemia (39%) and neutropenia (31%). In 60 patients that received the recommended step-up regimen, 53% experienced CRS. All cases were resolved with supportive measures, with a median duration of 2 days (range: 1 to 7 days). No events of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported.
