Introduction: Venetoclax + rituximab (VR) is a standard-of-care therapy for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, an unmet need remains for more effective treatments. Nemtabrutinib is a noncovalent, reversible, competitive Bruton tyrosine kinase inhibitor (BTKi) that has shown manageable safety and durable antitumor activity in participants with CLL/SLL with and without C481 mutations in the BELLWAVE-001 study. The active-controlled, open-label, randomized, 2-part, phase 3 BELLWAVE-010 study (NCT05947851) was designed to investigate the safety and efficacy of nemtabrutinib + venetoclax versus VR as second-line or later treatment for participants with R/R CLL/SLL. Part 1 is a nonrandomized dose-escalation and confirmation phase to evaluate safety and tolerability, including dose-limiting toxicities (DLTs), and to establish the recommended dose of nemtabrutinib + venetoclax. Part 2 is a parallel-group, randomized phase to compare the efficacy and safety of nemtabrutinib + venetoclax with VR. We present results from part 1 of the study.

Methods: Eligible participants were aged ≥18 years with active CLL/SLL that is R/R to ≥1 prior therapy per International Working Group on chronic lymphocytic leukemia (iwCLL) 2018 criteria and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Nemtabrutinib was administered at 2 doses (45 mg escalating to 65 mg by mouth [PO] once daily [QD]) for 4 weeks, then nemtabrutinib + venetoclax (20-400 mg PO QD escalating over 28 days). In part 2, participants would receive nemtabrutinib + venetoclax (dosing consistent with part 1) or VR. Primary end points for part 1 were safety and tolerability. Efficacy end points for part 1 included objective response rate (ORR) and duration of response. The data cutoff date was April 9, 2025.

Results: As of the data cutoff date, 31 participants were enrolled in the DLT evaluable population in part 1; 15 received nemtabrutinib 45 mg + venetoclax and 16 received nemtabrutinib 65 mg + venetoclax. The median study follow-up for the DLT evaluable population was 10.3 months (range, 1.2-19.4). The median age was 70 years (range, 39-89), 22 participants (71%) were male, 5 (16%) had received ≥3 prior lines of therapy, and 3 (10%) had an ECOG PS of 2. Of the 31 participants in the DLT evaluable population, 2 (6%) discontinued treatment due to an AE. Two participants who received nemtabrutinib 65 mg experienced a DLT (both pneumonia: 1 grade 3 [resolved] and 1 grade 5). Treatment-related AEs of any grade were reported for all 15 participants (100%) in the nemtabrutinib 45 mg arm and all 16 participants (100%) in the nemtabrutinib 65 mg arm; grade 3-5 treatment-related AEs occurred in 11 (73%) and 12 (75%) participants, respectively. Death due to a treatment-related AE occurred in 1 participant (6%) in the nemtabrutinib 65 mg arm (pneumonia); no deaths were reported in the nemtabrutinib 45 mg arm. The most common treatment-related AEs of any grade for the nemtabrutinib 45 and 65 mg arms (incidence ≥40% in either arm) were neutropenia (53% and 50%), diarrhea (40% and 19%), and thrombocytopenia (40% and 44%). The ORR was 100% (95% CI, 78%-100%) in the nemtabrutinib 45 mg arm, with a complete response (CR) rate of 13% and a PR rate of 87%. The ORR in the nemtabrutinib 65 mg arm was 88% (95% CI, 62%-98%), with a CR rate of 13% and a PR rate of 75%. Median duration of response was not reached in both arms. The maximum percent change from baseline of target lesions sum of product of diameters was >50% in 93% of participants in both arms. Efficacy outcomes are still maturing due to short follow up time.

Conclusion: Initial results for part 1 of the BELLWAVE-010 study showed that nemtabrutinib + venetoclax had very promising antitumor activity with 100% response rate for the 45 mg nemtabrutinib dose and a manageable safety profile, supporting the ongoing evaluation of this combination in pts with R/R CLL/SLL. Minimal residual disease analysis is currently ongoing.

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2025
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