– Regeneron Pharmaceuticals, Inc. (NASDAQ:REGN) today announced positive new and updated data from a Phase 1 and pivotal Phase 2 trial (ELM-1 and ELM-2) evaluating investigational odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). These included first data from a Phase 2 cohort of patients naïve to prior CAR-T therapy (CAR-T naïve), as well as updated data from a dose expansion cohort of a Phase 1 trial in patients who had progressed on CAR-T therapy (post-CAR-T). The results were presented in an oral session at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, LA, and will form the basis of planned submissions to regulatory authorities in 2023, including to the U.S. Food and Drug Administration (FDA). Odronextamab is an investigational bispecific antibody designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing.
“People with diffuse large B-cell lymphoma face a disease that often relapses and becomes more aggressive each time it returns, leaving doctors with a shrinking set of treatment options,” said Won Seog Kim, M.D., Ph.D., Samsung Medical Center and Division of Hematology-Oncology at Sungkyunkwan University, in Seoul, South Korea, and trial investigator. “The Phase 1 and pivotal Phase 2 odronextamab data demonstrated deep and durable responses that were consistent in patients who progress after CAR-T therapy, which is important as they have particularly difficult-to-treat disease and no effective treatment options. Coupled with its overall safety profile, these clinically important results reinforce the potential of odronextamab to treat this aggressive blood cancer.”
At ASH, efficacy in R/R DLBCL was presented from 130 CAR-T naïve patients in a Phase 2 cohort (includes those with an opportunity for assessment at 12 weeks; median follow-up: 21 months, range: 3 to 30 months) and 31 CAR-T experienced patients in a dose expansion cohort of a Phase 1 trial (median follow-up: 24 months, range: 3 to 38.5 months). All patients had received at least two prior therapies, including a CD20 antibody and alkylating agent. Patients were treated with a step-up regimen of odronextamab in the first cycle to help mitigate the risk of cytokine release syndrome (CRS) before receiving the full dose of 160 mg. The step-up regimen was modified part way through the trial to further mitigate CRS. Results as assessed by independent central review were as follows:
Among CAR-T naïve patients, a 49% objective response rate (ORR), with 31% achieving a complete response (CR). The median duration of complete response (mDOCR) was 18 months (95% confidence interval [CI]: 10 months to not evaluable [NE]).
Among post-CAR-T patients, a 48% ORR, with 32% achieving a CR. The mDOCR was not reached (95% CI: 2 months to NE).
Among 140 patients in the Phase 2 cohort assessed for safety, adverse events (AE) occurred in 99% of patients, with 79% being ≥Grade 3. The most common AEs occurring in ≥20% of patients were CRS (55%), anemia (42%), pyrexia (39%), neutropenia (28%) and hypokalemia (20%). Discontinuations due to an AE occurred in 10% of patients, and there were 5 deaths due to pneumonia (n=3), COVID-19 (n=1) and pseudomonal sepsis (n=1) where the relationship to odronextamab treatment could not be excluded.
CRS was the most common AE, of which 64% of cases were mild (Grade 1) and all resolved within a median time of 2 days (range: 1-133 days). There were no Grade 4 or 5 CRS cases, and the incidence of Grade 2 or higher cases was reduced with the modified step-up regimen when compared to the original (original regimen n=67 vs. step-up regimen n=73; Grade 2: 18% vs. 14%, Grade 3: 7.5% vs. 1%).
Based on these data, the OLYMPIA Phase 3 development program investigating odronextamab in earlier stages of the disease is in the process of being initiated. In the U.S., odronextamab has been granted Fast Track Designation for DLBCL by the FDA. In the European Union, Orphan Drug Designation was granted for DLBCL by the European Medicines Agency. Odronextamab is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.
