Bexobrutideg (NX-5948), a novel BTK degrader, shows high clinical activity and tolerable safety in an ongoing Phase 1a/b study in Waldenström macroglobulinemia
Introduction/Background/Significance: The B-cell receptor signaling pathway mediated by BTK is a validated therapeutic target in Waldenström macroglobulinemia (WM). Bexobrutideg is a novel, 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 findings from an ongoing Phase 1a/b trial of bexobrutideg in patients with WM who have progressed after multiple lines of therapy, including BTKi.
Materials and Methods/Case Presentation/Objective: NX-5948-301 is a Phase 1, first-in-human, dose-escalation trial evaluating safety/tolerability and activity of bexobrutideg in relapsed/refractory B-cell malignancies, including CLL/SLL and NHL/WM, in parallel 3+3 dose-escalation and dose-expansion cohorts. Key eligibility criteria: 2 prior lines of treatment; ECOG PS 0–1. Primary objectives: evaluation of safety/tolerability; identification of recommended Phase 2 dose. Key secondary objectives: characterization of PK/PD profile; assessment of preliminary efficacy (IWWM-6 criteria).
Results/Description/Main Outcome Measures: As of the 12 March 2025 cutoff, 22 patients with WM were enrolled and were treated at four daily oral dose levels: 200 mg (n=1), 300 mg (n=3), 450 mg (n=2), 600 mg (n=16). Median age was 72.5 (range 58–86) years; 81.8% of patients were male; patients had received a median of 3 (range 2–5) prior lines of therapy, including: cBTKi (100%); ncBTKi (18.2%); BTKi+BCL2i (4.5%); chemo/chemoimmunotherapy (95.5%). Site-reported mutation rates were: MYD88 (68.2%); CXCR4 (22.7%).
Bexobrutideg was well tolerated across all doses, consistent with previous reports. Median follow-up was 3.7 (range 1.9–18.9) months. Most common TEAEs were: petechiae (27.3%, no Grade ≥3); diarrhea (22.7%; no Grade ≥3); purpura/contusion (18.2%, no Grade ≥3); neutropenia (18.2%; 4.5% Grade ≥3); thrombocytopenia (18.2%; 4.5% Grade ≥3), and upper respiratory tract infection (18.2%; no Grade ≥3). There were no DLTs, two TEAEs resulting in drug discontinuation, two related SAEs but no Grade 5 AEs and no atrial fibrillation.
In 19 response-evaluable patients with WM, ORR was 84.2% (2 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 rapid and steady decrease in IgM levels from baseline was observed in most patients. Responses deepened with longer time on treatment, with 2 responses deepening to VGPR with longer duration on treatment. 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. Three patients had a 90%+ reduction in IgM levels. Durable responses were seen regardless of prior therapy or baseline mutations. Eight patients have reached >6 months on study, and two have reached >18 months on study.
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 in heavily pre-treated patients, and in patients whose tumors had MYD88 and CXCR4 mutations. Bexobrutideg Phase 1b dose expansion is underway.
