Bexobrutideg (NX-5948), a novel BTK degrader, demonstrates rapid and durable clinical responses in relapsed/refractory CLL: updated findings from ongoing Phase 1a study
Introduction/Background/Significance: Although BTK inhibitors (BTKi) are effective in chronic lymphocytic leukemia (CLL), the emergence of BTKi resistance mutations and identification of kinase-independent signaling via BTK scaffolding function underscores the need for new approaches. 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. We report updated findings from a Phase 1a trial of bexobrutideg in patients with relapsed/refractory (R/R) CLL.
Materials and Methods/Case Presentation/Objective: NX-5948-301 is a Phase 1, first-in-human trial of bexobrutideg in R/R B-cell malignancies, including CLL and NHL/WM, in parallel 3+3 dose-escalation (1a) and dose-expansion (1b) cohorts. Key eligibility criteria: ≥2 prior therapy lines; 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 (iwCLL criteria).
Results/Description/Main Outcome Measures: As of the 12 March 2025 cutoff, the Phase 1a cohort was fully enrolled including 48 patients with CLL/SLL treated at 6 daily oral dose levels: 50 mg (n=3), 100 mg (n=5), 200 mg (n=9), 300 mg (n=8), 450 mg (n=7), 600 mg (n=16). Median age was 68.5 (range 35–88) years; 66.7% of patients were male; patients had received a median of 4 (range 2–12) prior lines of therapy, including: cBTKi (97.9%), ncBTKi (27.1%), BCL2i (83.3%), BTKi+BCL2i (81.3%), chemo/chemoimmunotherapy (72.9%), PI3Ki (29.2%), CAR-T (6.3%). In 47 patients with genetic testing available, mutations were: TP53 (44.7%), BTK (38.3%), PLCG2 (14.9%), and BCL2 (12.8%).
Bexobrutideg was well tolerated across all doses in the Phase 1a CLL cohort (n=48), consistent with the overall study safety population. Median follow-up was 9.0 (range 1.6–26.1) months. There were no DLTs; 1 patient discontinued due to a TEAE. The most common TEAEs were: purpura/contusion (45.8%, no Grade ≥3); diarrhea (31.3%, 4.2% Grade ≥3); fatigue (31.3%, no Grade ≥3); neutropenia (29.2%, 22.9% Grade ≥3); rash (27.1%, 2.1% Grade ≥3, 2.1% SAE), petechiae (25.0%, no Grade ≥3), and headache (25.0%, no Grade ≥3). One Grade 5 event (pulmonary embolism, unrelated to bexobrutideg) occurred in a patient with a history of atrial fibrillation. No systemic fungal infections or new onset atrial fibrillation were observed.
In 47 response-evaluable patients with CLL, the ORR was 80.9% (1 CR and 37 PR). Responses were rapid with a median time to first response of 1.9 (range 1.6–11.1) months. Median duration of response has not been reached. Eighteen patients have reached >12 months on study, and 5 patients >18 months. Durable responses were seen regardless of prior treatments, mutation status, or CNS involvement.
Conclusions: Bexobrutideg was well tolerated in patients with R/R CLL, including those with longer duration of treatment and higher doses. Bexobrutideg showed rapid and durable responses independent of prior treatment or high-risk features. Phase 1b dose-expansion cohort enrollment is complete; enrollment is ongoing in additional Phase 1b sub-population cohorts and pivotal trial(s) initiation is planned later in 2025.
