Updated analysis of the first-in-human phase 1/2 trial showed that BCMA x CD3 bispecific monoclonal antibody REGN5458 monotherapy resulted in early, deep, and durable responses with an acceptable safety and tolerability profile in heavily pretreated patients with RRMM.
The ongoing, first-in-human, phase 1/2 trial (NCT03761108) evaluated the safety and antitumor activity of the B-cell maturation antigen (BCMA) x CD3 bispecific monoclonal antibody REGN5458 in heavily pretreated patients with at least triple-refractory relapsed/refractory multiple myeloma (RRMM). Updated safety, overall response, and response durability of patients treated in the phase 1 portion of this study were reported at the 2021 ASH Annual Meeting and summarized here.
The study enrolled patients with progressive RRMM who were triple-refractory or intolerant to previous lines of systemic therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. Eligible patients received REGN5458 monotherapy using a modified 3+3 dose-escalation design (4+3). Treatment consisted of 16 weekly infusions of REGN5458, followed by biweekly dosing until disease progression. The primary objectives of the phase 1 portion of the study were to assess the safety, tolerability, and occurrence of dose-limiting toxicities of REGN5458 and to determine a recommended phase 2 dose regimen. Key secondary end points were investigator-assessed objective response rate, duration of response (DOR), minimal residual disease status, pharmacokinetic analysis, and immunogenicity. The data cutoff date was September 30, 2021.
The dose-escalation cohort included 73 patients who received REGN5458 treatment across full doses ranging from 3 mg to 800 mg. The median age of the study cohort was 64 years; 21% of patients were aged ≥75 years, and 58% had Revised Multiple Myeloma International Staging System stage II and 23% had stage III. Patients had received a median of 5 previous lines of systemic therapy, and 38% were penta-refractory. The median duration of follow-up was 3 months.
Overall, the safety profile was consistent across all REGN5458 dose levels tested. Treatment-emergent adverse events (TEAEs) of any grade occurred in 100% of patients. The most common TEAEs included fatigue (45%), pyrexia (36%), and nausea (33%), which were mostly grade 1/2 severity. Treatment-related adverse events (TRAEs) occurred in 82.4% of patients; the most common hematologic TRAE was neutropenia (16.2%; grade ≥3, 13.2%) and the most common nonhematologic TRAEs were cytokine release syndrome (CRS; 38.2%) and fatigue (20.6%). Grade ≥3 TEAEs occurred in 42% of patients. CRS was reported in 28 (38%) patients, which were all grade 1/2; none discontinued treatment as a result of CRS. There were no grade ≥3 CRS or neurotoxicity events. There was no correlation between CRS and the full dose of REGN5458.
While responses were achieved across all dose levels, a response rate of 75% (18 of 24) was achieved among patients treated at the 200- to 800-mg dose levels. Across all dose levels, at least a very good partial response was achieved by 86% (N = 32) of all responders and complete response/stringent complete response was achieved by 43% (N = 16) of responders. The patient subgroup without extramedullary plasmacytomas achieved higher responses than those with extramedullary plasmacytomas. Median DOR was not reached; a high probability (90.2%) of DOR ≥8 months was estimated. Disease response did not correlate with BCMA expression levels.
Updated analysis of the phase 1/2 trial was promising, showing that REGN5458 monotherapy resulted in early, deep, and durable responses with an acceptable safety and tolerability profile in heavily pretreated patients with RRMM.
Source: Zonder JA, Richter J, Bumma N, et al. Early, deep, and durable responses, and low rates of cytokine release syndrome with REGN5458, a BCMAxCD3 bispecific monoclonal antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma (RRMM). Blood. 2021;138(suppl 1):160.