Introduction: The B-cell receptor signaling pathway mediated by BTK is a validated therapeutic target in Waldenström macroglobulinemia (WM). Bexobrutideg is a novel, highly selective, orally administered small molecule degrader that induces removal of wild-type and mutant BTK through ubiquitination by the cereblon E3 ligase complex and subsequent proteasomal degradation. Bexobrutideg can overcome treatment-emergent BTK inhibitor (BTKi) resistance mutations and address kinase-independent signaling by eliminating BTK scaffolding function. We report updated results from patients with WM enrolled in an ongoing Phase 1a/b trial of bexobrutideg in patients with relapsed/refractory B-cell malignancies who have progressed after multiple lines of therapy.

Methods: NX-5948-301 is a Phase 1, first-in-human trial of bexobrutideg in relapsed/refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL)/WM, in parallel 3+3 dose-escalation (Phase 1a) and dose-expansion (Phase 1b) cohorts. Key eligibility criteria include ≥2 prior lines of therapy and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1. Primary objectives are evaluation of safety/tolerability and identification of a recommended Phase 2 dose. Key secondary objectives include characterization of the PK/PD profile and assessment of preliminary efficacy according to International Workshop on WM (IWWM) criteria.

Results: As of the 27 May 2025 cutoff, 27 patients with WM were enrolled and treated at four daily oral dose levels: 200 mg (n=1), 300 mg (n=3), 450 mg (n=2), 600 mg (n=21). Median age was 73.0 (range 54–88) years; 81.5% of patients were male; and patients had received a median of 3 (range 1–5) prior lines of therapy, including: covalent BTKi (cBTKi, 100%); non-covalent BTKi (ncBTKi, 14.8%); BTKi+BCL2i (7.4%); chemo/chemoimmunotherapy (88.9%). Site-reported mutation rates (based on historical data) were MYD88 (74.1%) and CXCR4 (18.5%). There were 2 patients with CNS involvement (Bing-Neal).

Bexobrutideg was well tolerated across all doses, consistent with previous reports. Median follow-up was 7.3 (range 3.0–21.4) months. Most common TEAEs were: diarrhea (29.6%; no Grade (Gr) ≥3); petechiae (25.9%, no Gr ≥3); purpura/contusion (18.5%, no Gr ≥3); neutropenia (18.5%; 7.4% Gr ≥3); and upper respiratory tract infection (18.5%; no Gr ≥3). There were no DLTs, 2 TEAEs resulting in drug discontinuation (Gr 1 subdural hematoma; Gr 2 fungal infection), 4 treatment-related SAEs in 2 patients (Gr 1 subdural hematoma, Gr 3 influenza, Gr 3 epistaxis, Gr 3 gingival bleeding), no Gr 5 AEs and no clinically significant atrial or ventricular arrythmia.

In 20 response-evaluable patients with WM, ORR was 85.0% (3 VGPR, 11 PR, 3 MR, 3 SD, 0 PD). Bexobrutideg produced robust, rapid and sustained BTK degradation in all patients at all dose levels. A steady reduction in IgM levels occurred in most patients starting from the first IgM assessment (4 weeks), which continued to deepen at 8 weeks and beyond. Median time to first response was 1.84 (0.8–5.9) months. Median reduction in IgM levels was 79.6% (4.1–95.9), and 42.9% (9/21) of patients had 90% or greater reduction in IgM or normalized IgM levels. Responses deepened with longer time on treatment, with 3 responses deepening to VGPR and the earliest time to VGPR was 3.3 months. 12 patients have reached >6 months on study (10/12 still on treatment), and 2 patients have reached >18 months on study (both still on treatment). Both patients with Bing-Neal syndrome remain on study with stabilization of their CNS disease, and a partial response to their systemic disease (95.2% and 88.7% reduction in IgM).

Conclusions: Bexobrutideg was well tolerated in patients with WM, consistent with previous disclosures in the overall study population. Bexobrutideg demonstrated a notably high level of clinical activity with steady reduction in IgM levels and deepening responses over time in heavily pre-treated patients (all of whom had prior cBTKi exposure), and in patients whose tumors had MYD88 and CXCR4 mutations. Bexobrutideg Phase 1b dose expansion is underway.

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2025
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