Background: Targeting the Bruton’s tyrosine kinase (BTK) pathway has been a revolutionary treatment option for first-line treatment of CLL/SLL. Nemtabrutinib is a noncovalent, reversible, potent BTK inhibitor that targets both wild-type and C481S-mutant BTK. Results of an ongoing phase 1/2 dose-escalation study (BELLWAVE-001) have demonstrated manageable safety and preliminary antitumor activity of nemtabrutinib in pts with CLL/SLL. BELLWAVE-008 is a randomized, open-label, phase 3 study (NCT05624554) designed to evaluate efficacy and safety of nemtabrutinib compared with investigator’s choice of chemoimmunotherapy (FCR or BR) in pts with previously untreated CLL/SLL without TP53 aberrations. Methods: Eligible pts are ≥18 years old with previously untreated CLL/SLL with active disease and without TP53 aberrations (17p deletion and/or TP53 mutation), with ECOG PS of 0-2 and adequate organ function. Pts with Richter transformation or active central nervous system involvement are excluded. Approximately 300 pts will be enrolled and randomly assigned 1:1 to receive nemtabrutinib (65 mg orally once daily until progressive disease, unacceptable toxicity, or discontinuation) or intravenous infusion of the investigator’s choice of chemoimmunotherapy for 6 cycles lasting 28 days each (FCR: fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² on days 1, 2, and 3 of each cycle, plus rituximab 375 mg/m² initially, followed by 500 mg/m² on day 1 of each cycle; or BR: bendamustine 70-90 mg/m² on days 1 and 2 of each cycle plus rituximab 375 mg/m² initially, followed by 500 mg/m² on day 1 of each cycle). Randomization will be stratified by risk (high risk: 11q deletion and/or IGHV unmutated vs low risk: absence of high-risk factors) and age ( < 65 years vs ≥65 years). Treatment response (imaging, physical examination, constitutional symptoms, hematologic evaluation, and bone marrow biopsy, as required) will be performed every 12 weeks up to and including cycle 25, and every 24 weeks thereafter. Adverse events (AEs) will be monitored up to 30 days after treatment cessation (90 days for serious AEs) and will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and hematologic toxicities will be evaluated according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL). Primary end point is progression-free survival per the iwCLL 2018 criteria as assessed by blinded independent central review. Secondary end points include overall survival, objective response rate (ORR), duration of response, and safety. Exploratory efficacy end points include resistance evaluations, ORR including partial response with lymphocytosis as a response category, pharmacokinetics/pharmacodynamics, and health-related quality of life. Enrollment is ongoing. Clinical trial information: NCT05624554.