REGN5458 Elicits Early, Sustainable Responses in Heavily Pretreated Multiple Myeloma

The bispecific antibody REGN5458 elicited rapid responses that were further characterized by their depth, durability, and low incidence of cytokine release syndrome (CRS) in patients with relapsed/refractory multiple myeloma, according to findings from a phase 1/2 study (NCT03761108) that were presented during the 2022 EHA Congress.

The overall response rate (ORR) was 51% among all enrolled patients (n = 73). Among all responders, 86% achieved a very good partial response (VGPR) or better and 43% achieved a complete response (CR) or better.

“Overall, we have very promising data, and a very acceptable safety profile. We believe that these results will support further therapy [development] both as monotherapy and future studies looking [at the agent] in combination,” study author Joshua Richter, MD, associate professor of medicine, hematology and medical oncology at The Tisch Cancer Institute and director of Multiple Myeloma at the Blavatnik Family- Chelsea Medical Center at Mount Sinai in New York, New York, said in a presentation of the data.

Patients with multiple myeloma who are refractory to multiple treatment classes have a poor prognosis, with a median progression-free survival (PFS) of approximately 3 to 5 months and overall survival (OS) of 6 to 15 months.

REGN5458 is a BCMA- and CD3-directed bispecific antibody that targets T-cell effector function, resulting in cytotoxicity of BCMA-expressing multiple myeloma cells.

The first-in-human, open-label study enrolled patients with active multiple myeloma per International Myeloma Working Group criteria. Patients had to have relapsed disease or be refractory or intolerant to at least 3 lines of therapy including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody, or be double refractory to an IMiD and PI and have progressed on or after an anti-CD38 antibody. Patients with non-secretory multiple myeloma were permitted to enroll.

The primary objectives of the phase 1 dose-escalation portion were to establish the safety, tolerability, dose-limiting toxicities (DLTs), and recommended phase 2 dose of REGN5458. Analyzed as secondary objectives in the phase 2 dose-expansion portion were the ORR, duration of response (DOR), PFS, minimal residual disease (MRD) status, and OS.

Nine dose levels were evaluated in a 4+3 design: 3 mg (n = 4), 6 mg (n = 10), 12 mg (n = 10), 24 mg (n = 10), 48 mg (n = 7), 96 mg (n = 8), 200 mg (n = 12), 400 mg (n = 8), and 800 mg (4).

The drug was administered intravenously with a double step-up dosing pattern such that patients received an initial dose in week 1, another step-up dose in week 2, and the full cohort dose in week 3. From week 3 through week 16, patients received the cohort dose on a weekly basis, after which patients received the cohort dose every 2 weeks until disease progression or intolerability.

Regarding baseline characteristics, the median patient age was 64 years (range, 41-81), and 21% of patients were at least 75 years of age. Approximately half of patients (47%) were male and most had an ECOG performance status of 1 (70%), a Revised International Staging System score of II (58%), and prior autologous transplant (64%).

Bone marrow plasma cell burden of at least 50% was present in 39% of patients and 18% had high-risk cytogenetics.

The median number of prior lines of therapy was 5 (range, 2-17). Most patients were triple-refractory (89%) or quad-refractory (70%); 38% were penta-refractory and 90% were refractory to their last line of therapy.

Additional results indicated that when broken down by dose level, the ORR was 29% in the 3 mg to 12 mg cohort (partial response [PR], 4%; CR, 13%; stringent CR [sCR], 13%), 48% in the 24 mg to 96 mg cohort (VGPR, 24%; CR, 4%; sCR, 20%), and 75% in the 200 mg to 800 mg cohort (PR, 17%; VGPR, 42%; CR, 8%; sCR, 8%).

Notably, 4 of 10 patients who achieved a CR/sCR who had available MRD data achieved MRD negativity at a sensitivity of 10^–5.

The median time to response was less than 1 month, and 70% of responses occurred in the first 2 months of treatment. The estimated median DOR was not reached, although the estimated probability of responders being in response at 8 months was 90.2% (95% CI, 72.6%-96.7%).

As of the data cutoff of September 30, 2021, the longest responses had been ongoing for more than 19 months.

The maximum-tolerated dose was not reached, although DLTs occurred in 2 patients at the 24 mg and 96 mg doses.

All-grade treatment-emergent adverse effects (TEAEs) occurred in 100% of patients (grade 3, 42%; grade 4, 33%).

Hematologic TEAEs occurring in at least 20% of patients included anemia (all grade, 32%; grade 3, 23%), lymphopenia (all grade, 23%; grade 3, 10%; grade 4, 10%), neutropenia (all grade, 23%; grade 3, 7%; grade 4, 15%), and thrombocytopenia (all grade, 21%; grade 3, 8%; grade 4, 5%).

Nonhematologic TEAEs occurring in at least 20% of patients included fatigue (all grade, 45%; grade 3, 3%), CRS (all grade, 38%), pyrexia (all grade, 36%; grade 3, 4%), nausea (all grade, 33%), dyspnea (all grade, 26%), diarrhea (all grade, 25%; grade 3, 3%), back pain (all grade, 25%; grade 3, 5%), vomiting (all grade, 25%), pneumonia (all grade, 23%, grade 3, 11%), chills (all grade, 22%; grade 3, 1%), cough (all grade 22%), and headache (all grade, 21%; grade 3, 3%).

Three patients (4%) experienced grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS); notably, no grade 3 ICANS events were reported.

Five (7%) grade 5 AEs occurred due to sepsis (n = 3), COVID-19 (n = 1), and pneumonia (n = 1); all deaths were determined to be unrelated to study treatment.

Across the study population, 38% of patients developed CRS. Most CRS events were grade 1 (n = 25), and only 3 patients (4%) experienced grade 2 CRS; no grade 3 or greater CRS events occurred.

Broken by dose level, 38% (grade 1, n = 9) of patients experienced CRS in the 3 mg to 12 mg cohort, 36% (grade 1, n = 6; grade 2, n = 3) in the 24 mg to 96 mg cohort, and 42% (grade 1, n = 10) in the 200 mg to 800 mg cohort.

The median time to onset of CRS was 10.1 hours (range, 6-47) and the median duration was 14.7 hours (range, 0-96). Supportive care for CRS included tocilizumab (Actemra; 43%) and steroids (21%).

Notably, no association between CRS and dose level, or CRS and response was found.

Richter added that pharmacokinetic analysis revealed a correlation between REGN5458 serum concentration and dose.

“We are seeing early, deep, and durable responses with the Regeneron 5458 BCMA- and CD3-directed bispecific antibody in patients who are at least triple refractory to prior therapy,” Richter concluded.

The phase 2 portion of the study is open for recruitment.

Reference

Zonder JA, Richter J, Bumma N, et al. Early, deep, and durable responses, and low rates of CRS with REGN5458, a BCMAXCD3 bispecific antibody, in a phase 1/2 first-in-human study in patients with relapsed/refractory multiple myeloma. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S189.