C094 | 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 WALDENSTRÖM MACROGLOBULINEMIA

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. We report clinical outcomes from an ongoing Phase 1a/b trial of bexobrutideg in patients with WM progressing after multiple lines of therapy (LoT), including BTKi. 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 with parallel 3+3 dose-escalation and dose-expansion cohorts. Key eligibility criteria: ≥2 prior LoT and ECOG PS 0–1. 1’ objectives: safety/tolerability and identification of a recommended Phase 2 dose. Key 2’ objectives: PK/PD and preliminary efficacy. As of 2 January 2025, 18 patients with WM were treated at 4 daily dose levels: 200 mg (n=1), 300 mg (n=3), 450 mg (n=2), 600 mg (n=12). Median age 73.5 (64–86) years, 83.3% male, median 3 (2–5) prior LoT, including: cBTKi (94.4%); ncBTKi (22.2%); BTKi+BCL2i (5.6%); chemo/chemoimmunotherapy (94.4%). Mutation rates: MYD88 (66.7%); CXCR4 (22.2%). Bexobrutideg was well tolerated across all doses. In patients with WM, the median duration of treatment was 3.8 (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 13 response-evaluable patients with WM, ORR was 84.6% (1 VGPR, 10 PR/MR, 2 SD, 0 PD). BTK degradation was robust, rapid and sustained. In addition, a rapid and steady decrease in IgM levels was observed. 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. Bexobrutideg was well tolerated in patients with WM, consistent with 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 despite all patients having prior BTKi exposure. Favorable outcomes were seen independent of baseline mutational status, including MYD88 and CXCR4 mutations. Bexobrutideg Phase 1b dose expansion is underway.