Nemtabrutinib (MK-1026) given in combination with venetoclax (Venclexta) demonstrated encouraging early clinical activity with a manageable safety profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from the part 1, dose-escalation and -confirmation portion of the phase 3 BELLWAVE-010 study (NCT05947851).1
Findings presented at the 2025 ASH Annual Meeting and Exposition showed that at a data cutoff of April 9, 2025, and a median follow-up of 10.3 months (range, 2.2-19.4) in the dose-limiting toxicity (DLT)–evaluable population, the overall response rate (ORR) per International Workshop on CLL (iwCLL) 2018 criteria by investigator assessment was 100% (95% CI, 78%-100%) among patients treated with nemtabrutinib at 45 mg plus venetoclax (n = 15) and 88% (95% CI, 62%-98%) among those who received nemtabrutinib at 65 mg plus venetoclax (n = 16).
In the 45-mg cohort, best overall responses included complete response (CR) in 13% of patients and partial response (PR) in 87% . In the 65-mg cohort, CR occurred in 13% of patients, and PR was reported in 75%; 13% had not yet undergone efficacy assessment at the time of data cutoff. Median duration of response was not reached in either cohort, with observed ranges of 10.0 to 14.1+ months in the 45-mg group and 3.0 to 8.3+ months in the 65-mg group.
Investigators noted that the median duration of treatment was longer in the 45-mg cohort compared with the 65-mg cohort (11.5 vs 7.6 months), a difference that coincided with the shorter follow-up and unevaluable responses in a subset of patients treated at the higher dose.
Regarding safety, 2 patients in the 65-mg cohort experienced DLTs. One patient had grade 3 pneumonia, which resolved, and the other patient had grade 5 pneumonia.
Based on the totality of safety and efficacy data from part 1, nemtabrutinib at 45 mg in combination with venetoclax was selected as the recommended phase 2 dose for continued evaluation in the part 2 of the study.
“In part 1 of the BELLWAVE-010 study, nemtabrutinib plus venetoclax provided promising antitumor activity in participants with CLL/SLL, with an ORR of 100% at the nemtabrutinib 45-mg dose,” lead study author Paolo Ghia, MD, PhD, and colleagues wrote in a poster presentation of the data.
Ghia serves as a professor in medical oncology at the Università Vita-Salute San Raffaele in Milan, Italy.
How was the BELLWAVE-010 study designed?
The phase 3 BELLWAVE-010 study is evaluating nemtabrutinib in combination with venetoclax in patients with relapsed/refractory CLL/SLL via a dose-escalation and -confirmation design. The reported findings were from part 1 of the study, which focused on characterizing safety, tolerability, and preliminary efficacy of the regimen.1,2
Key Findings From BELLWAVE-010
- Nemtabrutinib plus venetoclax showed strong early activity in relapsed/refractory CLL/SLL, with an ORR of 100% at the 45-mg dose and 88% at the 65-mg dose in part 1 of the phase 3 BELLWAVE-010 study.
- Responses were deep and durable across dose levels, with CRs observed in 13% of patients in both cohorts, and the median DOR was not reached at the time of analysis.
- Based on efficacy, safety, and longer treatment duration, nemtabrutinib 45 mg plus venetoclax was selected as the recommended phase 2 dose for ongoing evaluation.
Eligible patients had CLL/SLL requiring treatment per iwCLL criteria and had received prior therapy.1 In the dose-escalation segment, patients received nemtabrutinib at either 45 mg or 65 mg orally once daily starting in cycle 1. Venetoclax was introduced in cycle 2 with a protocol-specified ramp-up to reduce tumor lysis syndrome (TLS) risk, with a target dose of 400 mg starting in cycle 3. Treatment was administered in 28-day cycles, with nemtabrutinib given continuously.
The dose-escalation phase was designed to evaluate safety and identify a recommended dose for further study, with DLTs assessed during early cycles. Efficacy end points in part 1 included ORR and DOR, assessed by investigator review using iwCLL 2018 criteria. Patients were included in the DLT-evaluable population if they received at least 1 dose of study treatment and met protocol-defined criteria.
What were the baseline characteristics of patients treated with nemtabrutinib?
Baseline characteristics were generally balanced between the nemtabrutinib 45-mg (n = 15) and 65-mg (n = 16) dose cohorts in the DLT-evaluable population.
The median age was 70 years (range, 39-89) in the 45-mg cohort and 66 years (range, 41-83) in the 65-mg cohort; patients 65 years of age or older comprised 73% and 69% of each group, respectively. Most patients were male (45-mg group, 67%; 65-mg group, 75%). The majority of patients were White (93%; 88%), with smaller proportions identifying as Black or African American (7%;13%). Hispanic or Latino ethnicity was reported in 53% of patients in the 45-mg cohort and 56% in the 65-mg cohort.
At baseline, ECOG performance status was 0 in 67% of patients receiving nemtabrutinib at 45 mg and 50% of those receiving 65 mg; ECOG performance status of 1 was reported in 33% and 31% of patients, respectively, while ECOG performance status of 2 was observed only in the 65-mg cohort (19%).
CLL was the primary diagnosis for most patients (45-mg group, 93%; 65-mg group, 88%), with the remainder diagnosed with SLL. Based on CLL International Prognostic Index criteria, most patients had intermediate- to high-risk disease, with 40% of the 45-mg cohort and 19% of the 65-mg cohort classified as CLL-IPI 4-6.
High-risk TLS was reported in 33% of patients in each cohort, and bulky disease (>10 cm) was present in 27% of the 45-mg cohort and 25% of the 65-mg cohort.
One prior line of therapy was reported in 60% and 56% of the 45-mg and 65-mg cohorts, respectively; 2 prior lines in 27% and 25%, respectively; and 3 or more prior lines in 13% and 19%, respectively. Prior exposure to anti-CD20 antibodies was common (67%; 63%), as was prior treatment with a BTK inhibitor (20%; 31%). Prior stem cell transplant was reported in 1 patient (6%) in the 65-mg cohort.
What additional safety data were reported?
Any-grade treatment-related adverse effects (TRAEs) occurred in all patients in both cohorts; the rates of grade 3 or higher TRAEs were 73% in the 45-mg group (n = 15) and 75% in the 65-mg group (n = 16). In the 45-mg group, TRAEs led to dose reductions, discontinuation of any drug, and death in 0%, 7%, and 0% of patients, respectively. In the 65-mg group, these respective rates were 31%, 6%, and 6%.
References
- Ghia P, Chandia Cabas M, Louw VJ, et al. Nemtabrutinib plus venetoclax in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the dose escalation and confirmation segment of the phase 3 BELLWAVE-010 study. Blood. 2025;146(suppl 1):2119. doi:10.1182/blood-2025-2119
- A study of nemtabrutinib plus venetoclax vs venetoclax plus rituximab in second-line and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (MK-1026-010/BELLWAVE-010). ClinicalTrials.gov. Updated December 25, 2025. Accessed January 12, 2026. https://www.clinicaltrials.gov/study/NCT05947851
