BEXOBRUTIDEG (NX-5948), A NOVEL BRUTON'S TYROSINE KINASE DEGRADER, SHOWS HIGH CLINICAL ACTIVITY AND TOLERABLE SAFETY IN AN ONGOING PHASE 1A/B STUDY IN PATIENTS WITH WALDENSTROM MACROGLOBULINEMIA.
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All Authors
El-Sharkawi, D.
Lewis, D.
Pulles, A.
Omer, Z.
Munir, T.
Collins, G.
Linton, K.
Alencar, A.
Gleeson, M.
McKay, P.
LTHT Author
Munir, Talha
LTHT Department
Oncology
Haematology
Haematology
Contributor Profession (Non Medical)
Publication Date
2025
Item Type
Conference Abstract
Language
Subject
Subject Headings
Abstract
Background The B-cell receptor signaling pathway mediated by Bruton's tyrosine kinase (BTK) is a key driver in oncogenesis and a validated therapeutic target in patients with Waldenstrom macroglobulinemia (WM). Bexobrutideg is a novel, orally administered small molecule degrader that induces removal of wild-type and mutant forms of 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 the scaffolding function of BTK. Aims Here we report clinical outcomes from an ongoing Phase 1a/b trial of bexobrutideg in patients with WM who have progressed after multiple lines of therapy, including BTKi, illustrating the role of BTK degradation in relapsed, refractory WM. Methods 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 doseexpansion cohorts. Key eligibility criteria include 2 prior lines of treatment and ECOG PS 0-1. Primary objectives are evaluation of the 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 IWWM-6 criteria. Results As of 2 January 2025, 18 patients with WM were enrolled and were treated at four daily dose levels: 200 mg (n=1), 300 mg (n=3), 450 mg (n=2), 600 mg (n=12). Median age was 73.5 (range 64-86) years, 83.3% were male, and patients had received a median of 3 (range 2-5) prior lines of therapy, including: cBTKi (94.4%); ncBTKi (22.2%); BTKi+BCL2i (5.6%); chemo/chemoimmunotherapy (94.4%). Site reported mutation rates were: MYD88 (66.7%); CXCR4 (22.2%). Bexobrutideg was well tolerated across all doses, consistent with previous reports. In patients with WM, the median duration of treatment was 3.8 (range 0.0-16.6) months. The most common TEAEs were: diarrhea (27.8%; no Gr>=3); thrombocytopenia (22.2%; 5.6% Gr>=3), purpura/contusion (22.2%, no Gr>=3); and petechiae (22.2%, no Gr>=3). There were no DLTs, 2 TEAEs resulting in drug discontinuation, and no atrial fibrillation was observed. In the 13 response-evaluable patients with WM, ORR was 84.6% (1 VGPR, 10 PR/MR, 2 SD, 0 PD). NX-5948 produced robust, rapid and sustained BTK degradation in all patients at all dose levels. In addition, a rapid and steady decrease in IgM levels from baseline was observed in most patients on treatment. Responses deepened with longer time on treatment, including conversions from MR to PR and PR to VGPR. Durable responses were seen regardless of prior therapy or baseline mutations. Five patients have reached >6 months on study, and 2 patients have reached >18 months on study. Summary/Conclusion 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 with WM despite all patients having prior BTKi exposure. Favorable outcomes were seen independent of baseline mutational status, including patients whose tumors had MYD88 and CXCR4 mutations. Bexobrutideg Phase 1b dose expansion is underway.
Journal
HemaSphere