Abstracts
PO68
DAYBreak CLL-201: A study of bexobrutideg (NX-5948), a BTK degrader, in patients with CLL/SLL previously treated with a covalent BTK inhibitor, a non-covalent BTK inhibitor and a BCL2 inhibitor
Paolo Ghia, MD – Università Vita-Salute San Raffaele, Milan, Italy; Dima El-Sharkawi, MD – Royal Marsden NHS Foundation Trust, Sutton, UK; Michal Kwiatek, MD – AidPort Hospital, Skórzewo (Poznan), Poland; Sebastian Grosicki, MD – Pratia Onkologia, Katowice, Poland; Anne Lok, MD – Centre Hospitalier Universitaire de Nantes, Nantes, France; Jane Robertson, MD – The Christie Hospital NHS Foundation Trust, Manchester, UK; Krish Patel, MD – Sarah Cannon Research Institute, Nashville, TN, USA; Iwona Hus, MD – Medical University of Lublin, Lublin, Poland; Leigh Beveridge, MD – Nurix Therapeutics, Inc., Brisbane, CA, USA; Srinand Nandakumar, MD – Nurix Therapeutics, Inc., Brisbane, CA, USA; Melissa Gessner, MD – Nurix Therapeutics, Inc., Brisbane, CA, USA; Wojciech Jurczak, MD – Maria Sklodowska-Curie National Research Institute of Oncology, Kraków, Poland
Introduction/Background/Significance:
Bruton's tyrosine kinase (BTK) plays a central role in the B-cell receptor (BCR) signaling pathway and is involved in the pathogenesis of several B-cell malignancies. While covalent BTK inhibitors (cBTKi), non-covalent BTKi (ncBTKi), and BCL-2 inhibitors (BCL2i) have transformed chronic lymphocytic leukemia (CLL) management, patients progressing after all three targeted classes represent a high unmet need with poor outcomes and limited standard options. 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 (NX-5948) is a novel, highly selective, orally administered small molecule protein degrader that induces the removal of wild-type and mutant forms of BTK through ubiquitination by the cereblon E3 ligase complex and subsequent proteasomal degradation. In a previous Phase 1 trial in relapsed/refractory (R/R) B-cell malignancies including CLL (NX-5948-301; NCT05131022), bexobrutideg was well tolerated and showed promising progression-free survival (PFS), rapid and durable responses, and a recommended Phase 2 dose of 600 mg once daily was identified.Materials and Methods/Case Presentation/Objective:
DAYBreak CLL-201 (NX-5948-201; NCT07221500) is a single-arm, open-label Phase 2 study designed to evaluate the efficacy and safety of bexobrutideg in adult patients with R/R CLL or small lymphocytic lymphoma (SLL) previously treated with a covalent BTKi, a non-covalent BTKi and a BCL2i. Key eligibility criteria include: histologically confirmed R/R CLL/SLL per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL; Hallek 2018); an Eastern Cooperative Oncology Group score of 0-2; prior exposure to a covalent BTKi, a non-covalent BTKi and a BCL2i (separate lines or in combination); measurable disease by radiographic assessment per iwCLL (≥1 lymph node with longest diameter >1.5 cm); adequate organ and bone-marrow function. Exclusion criteria include: known or suspected prolymphocytic leukemia or Richter's transformation; previous treatment with a BTK degrader; active second malignancy; and known central nervous system lymphoma or leukemia. Bexobrutideg 600 mg is given orally once daily, with response assessment every 8‒12 weeks. The primary endpoint is the objective response rate (ORR) without partial response with lymphocytosis (PR-L), per 2018 iwCLL criteria (as assessed by an independent review committee [IRC]). Secondary endpoints include the following additional efficacy outcomes: ORR with PR-L (as determined by IRC); ORR with/without PR-L (as determined by investigator); duration of response (IRC and investigator); PFS (IRC and investigator); complete response rate (IRC and investigator); time to response (IRC and investigator); and overall survival. Safety, pharmacokinetics and health-related quality of life will also be evaluated. Enrollment is underway and the study is expected to recruit ~100 patients globally.
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