REGN5458 is a bispecific antibody designed to bind to B-cell maturation antigen (BCMA) on multiple myeloma (MM) cells and the CD3 receptor on T-lymphocytes, thereby bridging them together and promoting immunologically mediated cancer cell death. Data showing an acceptable safety profile and preliminary clinical efficacy in a phase 1 trial in patients with relapsed/refractory (RR) MM were presented previously; updated safety and response durability data are now available. The primary objectives are to assess the safety, tolerability, and occurrence of dose-limiting toxicities (DLTs) of REGN5458; key secondary objectives include evaluation of overall response rate (ORR), duration of response (DOR), minimal residual disease status, pharmacokinetics, and pharmacodynamics.
The study enrolled patients with MM and progressive disease following ≥3 lines of systemic therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Patients were treated with REGN5458 weekly, followed by maintenance every 2 weeks, and the study followed a typical 4+3 dose-escalation design.
The current updated analysis includes 49 patients who received REGN5458. The median age was 64.0 years, and 31.0% (n = 15) of patients were aged >70 years. A total of 63.0% and 20.0% of patients were stage 2 and 3, respectively, based on the Revised International Staging System. Patients received a median of 5.0 prior lines of systemic therapy; 100% were triple-refractory, 57.0% were penta-refractory, and all patients were refractory to an anti-CD38 antibody. The majority of patients (67.0%; n = 33) had received a prior autologous stem-cell transplant. Dose escalation from 3 mg to 96 mg over 6 dose levels was performed in cohorts. Median duration of follow-up was 2.6 months.
Regarding treatment-related adverse events (TRAEs), 39.0% of patients experienced cytokine release syndrome (CRS), 35.0% experienced fatigue, and 31.0% experienced nausea. Most CRS events were grade 1 (84.0%) and were observed with the initial doses; no grade ≥3 events were observed. Two patients experienced a DLT: 1 due to transient grade 3 liver transaminases associated with CRS but the patient recovered and achieved partial remission, and 1 due to grade 4 acute kidney injury that resolved with supportive care. Discontinuation because of adverse events (AEs) occurred in 2 patients, 1 of whom had both a TRAE and a DLT of grade 4 acute kidney injury. The most common grade 3 TRAEs were anemia and neutropenia (22.0% and 14.0%, respectively). Three patients experienced grade 5 AEs (sepsis, 2; COVID-19, 1) unrelated to study drug.
Across all dose levels, the ORR was 35.6%, with 95.0% of patients achieving a very good partial response or better, and 42.0% of patients achieving a complete response or stringent complete response. The ORR was 62.5% at the highest dose level. A lower ORR was observed in patients with extramedullary plasmacytomas at 16.7%. Regarding duration, 37% of patients had a DOR ≥8 months.
Results from this updated analysis of a phase 1 first-in-human study of REGN5458 in heavily pretreated patients with RRMM are consistent with previous findings, which showed an acceptable safety profile and deep and durable responses. Continued assessment is warranted and ongoing, with enrollment for the phase 1 dose-escalation portion and recruitment for the phase 2 portion both underway.
Abstract 291. ASH 2020. December 5, 2020. REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM).