Initial Results from a Phase 1 Dose-Escalation Study of WVT078, a BCMA×CD3 Bispecific Antibody, in Combination with WHG626, a Gamma-Secretase (GS) Inhibitor, in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: WVT078, a potent anti–B-cell maturation antigen (BCMA)×anti-CD3 bispecific antibody (BsAb), is being investigated as a single-agent and in combination with a GS inhibitor (GSI), WHG626 (AL102), in patients (pts) with relapsed and/or refractory (r/r) multiple myeloma (MM). Single-agent WVT078 showed an acceptable safety profile in the ongoing first-in-human study with active dose range of 48-250 µg/kg (Raab, Leukemia 2023). Membrane BCMA expressed on surface of MM cells is cleaved by GS. This results in shedding of its extracellular domain (ECD) as soluble BCMA (sBCMA), which may bind to and interfere with activity of BCMA-targeting agents such as WVT078. By preventing this shedding, GSIs are postulated to increase clinical benefit of BCMA-targeting agents. WVT078 combined with WHG626 was shown to enhance anti-myeloma activity of WVT078 in vitro preclinically (Raab, Leukemia 2023), supporting rationale for this combination in r/r MM.

Methods: The combination of WVT078 and WHG626 is being investigated as part of above-mentioned phase 1 study (NCT04123418) in pts with MM who are r/r to ≥2 standard-of-care regimens, including an immunomodulatory drug, proteasome inhibitor, and anti-CD38 agent (if available). Pts who received prior BCMA chimeric antigen receptor T-cell therapy or BCMA antibody-drug conjugates therapy are included; pts with prior BCMA×CD3 BsAb treatment are excluded.

Primary objectives were to evaluate safety and tolerability and to determine recommended dose for expansion of WVT078 in combination with WHG626. Secondary objectives were to assess preliminary anti-tumor activity and characterize pharmacokinetics (PK) and immunogenicity. Key exploratory objectives included evaluation of sBCMA and characterization of immune-cell activation phenotypes. Dose escalation was guided by Bayesian Logistic Regression Model, and International Myeloma Working Group criteria were used to assess disease response. Flow cytometry was used to study pharmacodynamic (PD) effects on immunophenotype of immune cells. Immunoassay-based platform (Meso Scale Discovery) was used for assessing cytokine production and enzyme-linked immunosorbent assay for quantifying serum sBCMA levels.

Results: As of April 29, 2023, a total of 23 pts (median age, 64 years) with r/r MM were treated in dose escalation with intravenous WVT078 at 12-48 µg/kg once weekly, combined with oral WHG626 at 2-4 mg once daily, given 2 days on and 5 days off. Eighteen pts (78.3%) discontinued treatment due to progressive disease (n=15), adverse event (AE), guardian decision and physician decision (n=1 each). Most frequent (≥20%) treatment-related AEs across all doses in the combination were cytokine release syndrome (65.2%; Grade ≥3, n=1), pyrexia (39.1%), diarrhea (34.8%), decreased appetite (26.1%), hypophosphatemia, nausea and neutropenia (21.7% each); 5 pts experienced dose-limiting toxicities (pneumonia, neutropenia, ALT/AST/lipase increase, platelet count decrease, sepsis and shoulder pain). The safety profile is consistent with WVT078 and WHG626 as single agents. A maximum tolerated dose was not reached.

The overall response rate (partial response or better; ORR) and overall complete response (CR) rate (stringent CR+CR) across all dose levels tested were 39.1% (n=9; 90% CI, 22.2, 58.3) and 13.0% (n=3; 90% CI, 3.7, 30.4), respectively; ORR at two highest dose levels combined was 57.1% (n=8/14; 90% CI, 32.5, 79.4). PK total (AUC) and maximal (Cmax) exposure to WVT078 in serum increased approximately proportionally to dose in Cycle 1. Evidence of T-cell engagement with WVT078 was demonstrated by upregulated peripheral T-cell proliferation and activation markers. WHG626 decreased serum sBCMA levels by 10% within first 24 hours of treatment prior to WVT078 dosing. WHG626 enhanced WVT078-mediated increases in serum inflammatory cytokine levels, and upregulated T-cell activation phenotype in bone marrow in a dose-dependent manner. Based on preliminary data, cytokine and clinical effects were observed at lower WVT078 doses with WVT078+WHG626 than with WVT078 alone.

Conclusions: WVT078 combined with WHG626 has an acceptable safety profile and shows preliminary evidence of clinical activity at highest doses tested. PD biomarker analysis supports postulated mechanism of action of WHG626 combined with WVT078. This is the first clinical report on combination of BCMAxCD3 BsAb and GSI in r/r MM.