S189: 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

Abstract

Background: Despite recent advances in treatment options, multiple myeloma (MM) remains incurable. REGN5458 is a BCMAxCD3 bispecific antibody currently under investigation in relapsed/refractory MM (RRMM) in an ongoing Phase 1/2 trial (NCT03761108). Preliminary data suggest that REGN5458 has a manageable safety profile with early, deep and durable responses in heavily pretreated patients (pts). Aims: Here we describe updated safety, overall response and response durability in pts treated with REGN5458 in the Phase 1 portion of this ongoing trial. Methods: The Phase 1 primary objectives are to assess safety, tolerability and occurrence of dose-limiting toxicities of REGN5458 and to determine a recommended Phase 2 dose regimen (RP2DR). Key secondary objectives include: assessment of objective response rate as determined by the investigator, duration of response (DOR) and minimal residual disease status; pharmacokinetic evaluation; and characterization of immunogenicity. Pts with progressive RRMM, who are double- or triple-refractory, or intolerant to prior lines of systemic therapy including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody are treated with REGN5458 monotherapy following a modified 3 + 3 dose-escalation design (4 + 3). Treatment consists of 16 weekly infusions of REGN5458 followed by q2w dosing until disease progression. Response assessments are measured using modified International Myeloma Working Group criteria. Results: At data cut-off (September 30, 2021), 73 pts were treated with REGN5458 in the dose escalation cohort with full doses ranging from 3–800 mg. Median age at enrollment was 64 years (range, 41–81) and 20.5% pts were ≥75 years. As per Revised International Staging System, stage was 1, 2 or 3 in 15.0%, 57.5% and 23.3% of pts respectively. Pts had a median of 5 prior lines of systemic therapy (range, 2–17) with 38.4% of pts being penta-refractory (Table). Median duration of follow-up was 3.0 months (range, 0.7–22.1). Treatment-emergent adverse events (TEAE) were reported in 73 pts (100%), Grade (Gr) 3 in 31 pts (42.5%), Gr 4 in 24 pts (32.9%). The most common Gr 3/4 TEAEs were hematologic (39.0%). The most frequent TEAEs were fatigue in 33 pts (45.2%), Gr 1/2 in 31 pts (42.5%), Gr 3 in 2 pts (2.7%); cytokine release syndrome (CRS) in 28 pts (38.4%), Gr 1 in 25 pts (34.2%), Gr 2 in 3 pts (4.1%). No pt had Gr ≥3 CRS or discontinued treatment due to CRS. There were no Gr ≥3 neurotoxicity events. Nausea was reported in 24 pts (32.9%), Gr 1 in 17 pts (23.3%), Gr 2 in 7 pts (9.6%). Responses were observed at all dose levels. Across all dose levels, 86.5% (n=32/37) of all responders achieved at least a very good partial response and 43.2% (n=16) of responders had a complete response (CR) or stringent CR. Amongst pts treated at the 200–800 mg dose levels, the response rate was 75.0% (n=18/24). The Kaplan–Meier estimated probability of responders being in response for 8 months or more was 90.2% (95% confidence interval: 72.6–96.7), and median DOR was not reached. Image:Summary/Conclusion: REGN5458 shows a manageable safety and tolerability profile, with Gr 2 CRS in only 4.1% of pts and no Gr ≥3 CRS or neurotoxicity events. No new safety signals were observed during the additional follow-up period. Early, deep and durable responses were seen in triple- to penta-refractory pts with RRMM, with a 75.0% response rate at the combined 200–800 mg dose levels. The Phase 2 portion of the study is currently recruiting.