Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in Relapsed/Refractory chronic lymphocytic leukemia (CLL): New and updated findings from an ongoing Phase 1a/b trial

作者：Zulfa Omer, Alexey V. Danilov, Francesco Forconi, Talha Munir, Mary Gleeson, Nirav N. Shah, Graham P. Collins, Alvaro J. Alencar, Jane Robertson, Jonathon B. Cohen, Karan Dixit, Danielle M. Brander, John C. Byrd, Allison Winter, Jeffery Smith, Dima El‐Sharkawi, Michał Kwiatek, Iwona Hus, Prioty Islam, Sebastian Grosicki, Michael Tees, Thorsten Zenz, Joanna Romejko‐Jarosińska, Sarah G. Injac, Wojciech Jurczak · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-86 · 被引用次数：4 · 研究领域：Chronic Lymphocytic Leukemia Research、Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways

Abstract Introduction: Although BTK inhibition has proven to be a successful treatment modality in CLL, the emergence of BTK inhibitor (BTKi) resistance mutations and identification of kinase-independent signaling via the scaffolding function of BTK underscore the need for alternative approaches to target the totality of BTK protein functions. Bexobrutideg is a novel, highly selective, 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 new and updated findings from patients (pts) with relapsed/refractory CLL in a Phase 1 (Ph1) trial of bexobrutideg, including longer-term follow-up from the Ph1a cohort combined with first disclosure from the randomized Ph1b cohort. Methods: NX-5948-301 is a Ph1, first-in-human trial of bexobrutideg in relapsed/refractory B-cell malignancies, including CLL, consisting of 3+3 dose-escalation (Ph1a) followed by dose-expansion (Ph1b) cohorts. In Ph1b Cohort 1, pts were randomized between the 200 mg and 600 mg dose levels. Key eligibility criteria include ≥2 prior therapy lines (Ph1a) or prior exposure to both a BTKi and BCL2i (or deemed ineligible for BCL2i) (Ph1b). Primary objectives are evaluation of safety/tolerability and identification of a recommended Ph2 dose. Key secondary objectives include characterization of the PK/PD profile and assessment of preliminary efficacy. Results: As of 2...