Paper Details

ABSTRACT

Background: 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. Even though covalent (c) and non-covalent (nc) BTK inhibitors (BTKi) are effective in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), the emergence of BTKi resistance mutations and kinase-independent signaling via the scaffolding function of BTK highlight the need for alternative approaches to target 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 Phase 1 trial in patients with relapsed/refractory B-cell malignancies, including CLL/SLL (NX-5948-301; NCT05131022), bexobrutideg was well tolerated and demonstrated rapid and durable responses, and a recommended Phase 2 dose of 600 mg once daily (QD) was identified.

Methods: DAYBreak CLL-306 (NX-5948-306; NCT07516093) is a global, randomized, open-label, multicenter Phase 3 study evaluating the BTK degrader bexobrutideg versus the ncBTKi pirtobrutinib in adult patients with relapsed/refractory CLL/SLL who have progressed on or after cBTKi treatment. Approximately 620 patients will be randomized 1:1 to receive bexobrutideg 600 mg or pirtobrutinib 200 mg orally QD administered over 28-day continuous cycles until progression or intolerance. Patients will be stratified based on the presence of del(17p) and/or TP53 mutation, prior B-cell lymphoma-2 (BCL2) inhibitor therapy, and number of prior lines of therapy (≥4 vs <4). Key eligibility criteria include confirmed relapsed/refractory CLL/SLL per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines; an Eastern Cooperative Oncology Group Performance Score of 0–2; ≥1 prior line of therapy for CLL/SLL that included a cBTKi with documented disease progression during treatment with, or after discontinuation of, the cBTKi; and adequate organ/bone marrow function. Patients with SLL must have measurable disease by computed tomography (CT) per iwCLL 2018 guidelines. Exclusion criteria include: known/suspected prolymphocytic leukemia or Richter’s transformation; investigational agent or anticancer therapy within 5 half-lives or 14 days (whichever is shorter) prior to planned start of study treatment; ongoing systemic corticosteroids ≥10 mg/day prednisone or equivalent; prior treatment with a BTK degrader or ncBTKi; myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, placement of a coronary arterial stent, or any other significant cardiac condition within 6 months of planned start of study treatment; thromboembolic events, stroke, or intracranial hemorrhage within 6 months of planned start of study treatment; active second malignancy; and current or history of central nervous system involvement with CLL/SLL. Disease assessments will be performed every 12 weeks until Week 96 and every 24 weeks thereafter, with response assessed by an independent review committee (IRC) and by the investigator per iwCLL 2018 criteria. Progression-free survival (PFS) by IRC is a primary endpoint, and the trial is powered for PFS superiority. Secondary endpoints include additional efficacy measures (overall survival, PFS by investigator, overall response rate with and without partial response with lymphocytosis [PR-L], duration of response with and without PR-L, and time to next anti-CLL/SLL treatment), health-related quality of life (European Organization for Research and Treatment of Cancer Quality of Life Cancer Questionnaire C30 with CLL module [EORTC QLQ-C30 and QLQ-CLL17] and EuroQol-5 Dimensions, 5-level Questionnaire [EQ-5D-5L]), safety, and pharmacokinetics. The study is currently enrolling patients.