Nemtabrutinib Versus Ibrutinib or Acalabrutinib for Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The Phase 3, Open-Label, Randomized Bellwave-011 Study

Background: Ibrutinib and acalabrutinib are Bruton tyrosine kinase (BTK) inhibitors that have revolutionized the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL). However, treatment with ibrutinib and acalabrutinib is associated with uncommon substantial toxicities, drug resistance, and low complete remission rates. Therefore, an unmet need exists for treatment options with manageable safety profiles and better efficacy outcomes. Nemtabrutinib is a noncovalent, reversible, competitive inhibitor of both wild type and C481-mutated BTK. It has demonstrated manageable safety and promising antitumor activity in the phase 1/2 BELLWAVE-001 study in patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL). BELLWAVE-011 (NCT06136559) is an open-label, randomized, parallel-group, active-controlled, phase 3 study that is designed to determine the safety and efficacy of nemtabrutinib versus investigator’s choice of ibrutinib or acalabrutinib in patients with previously untreated CLL/SLL requiring therapy.

Study Design and Methods: Eligible patients are aged ≥18 years of age with confirmed CLL/SLL and active disease per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria, which include ≥1 of the following: progressive marrow failure or lymphocytosis; massive nodes or progressive or symptomatic lymphadenopathy; massive, progressive, or symptomatic splenomegaly; autoimmune complications, including anemia or thrombocytopenia that is poorly responsive to corticosteroids; symptomatic or functional extranodal involvement; and disease-related symptoms such as unintentional weight loss, significant fatigue, fever, or night sweats. Additionally, all patients must have an Eastern Cooperative Oncology Group performance status of 0 to 2 and be treatment naive. Key exclusion criteria include central nervous system involvement by CLL/SLL, a history of second malignancy or a severe bleeding disorder, and Richter transformation. Approximately 1200 patients will be randomly assigned 1:1 to receive nemtabrutinib 65 mg once daily by mouth (PO) or investigator’s choice of ibrutinib 420 mg once daily PO or acalabrutinib 100 mg twice daily PO. Treatment will continue in both arms until unacceptable toxicity, disease progression, withdrawal, or other discontinuation criteria are met. Treatment response assessment, including imaging, physical examination, constitutional symptoms, hematological evaluations, and bone marrow biopsy, will be performed every 12 weeks up to week 97 and every 24 weeks thereafter. Adverse events will be monitored throughout the trial and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and iwCLL 2018 criteria for hematologic toxicities. The primary end points are objective response rate and progression-free survival per iwCLL 2018 criteria by blinded independent central review. Secondary end points are overall survival, duration of response per iwCLL 2018 criteria by blinded independent central review, and safety and tolerability. Recruitment is ongoing.

©2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2024 ASCO Annual Meeting. All rights reserved.