Safety and Antitumor Activity of Nemtabrutinib Plus Venetoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia/small Lymphocytic Lymphoma: Part 1 of the Phase 3 Bellwave-010 Study
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: Background Venetoclax plus rituximab (VR) is a standard-of-care therapy for relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, the need for more effective treatments remains unmet. Nemtabrutinib is a reversible Bruton tyrosine kinase inhibitor that showed durable antitumor activity in participants with CLL/SLL in the phase 1/2 BELLWAVE-001 study. The open-label, randomized, phase 3 BELLWAVE-010 study (NCT05947851) is evaluating the safety and efficacy of nemtabrutinib plus venetoclax versus VR in R/R CLL/SLL. Herein, we present the results from part 1, the nonrandomized dose-escalation and confirmation phase of the study. Aim To evaluate the safety and efficacy of nemtabrutinib plus venetoclax. Materials and methods Participants aged ≥ 18 years with CLL/SLL R/R to ≥ 1 prior therapy per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria and an ECOG PS score of 0–2 received nemtabrutinib 45 or 65 mg orally once daily for 4 weeks, followed by nemtabrutinib + venetoclax (20–400 mg orally once daily escalated over 28 days). Primary end points were safety and tolerability, including dose-limiting toxicities (DLTs), and establishment of the recommended dose of nemtabrutinib plus venetoclax. Efficacy end points for part 1 were ORR and DOR per iwCLL 2018 criteria by BICR. Results As of the data cutoff date (April 9, 2025), 31 participants were enrolled in the DLT-evaluable population; 15 received nemtabrutinib 45 mg plus venetoclax and 16 received nemtabrutinib 65 mg plus venetoclax. Median study follow-up was 10.3 months (range, 1.2–19.4). 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 score of 2. Among the DLT-evaluable population, 2 (6%) discontinued treatment due to an AE. DLTs were reported in 2 participants with nemtabrutinib 65 mg (both pneumonia: one grade 3 [resolved] and one grade 5). Any-grade TEAEs were reported in all participants (100%) in both arms. Grade 3–5 TEAEs occurred in 11 participants (73%) in the nemtabrutinib 45-mg arm and 12 participants (75%) in the nemtabrutinib 65-mg arm. One death due to a TEAE occurred in the nemtabrutinib 65-mg arm (pneumonia); none occurred in the nemtabrutinib 45-mg arm. The most common TEAEs of any grade (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%; CR, 13%; PR, 87%) in the nemtabrutinib 45-mg arm and 88% (95% CI, 62%–98%; CR, 13%; PR, 75%) in the nemtabrutinib 65-mg arm. Median DOR was not reached in either arm. The maximum percent change from baseline of target lesions sum of product of diameters was > 50% in 93% of participants in both arms. Discussion: Although efficacy outcomes are still maturing due to short follow-up time, these initial results show promising antitumor activity for nemtabrutinib 45 mg plus venetoclax and a manageable safety profile. Conclusions These findings from part 1 of the ongoing phase 3 BELLWAVE-010 study support the ongoing evaluation of nemtabrutinib plus venetoclax in participants with R/R CLL/SLL.
Authors: Paolo GHIA, Mauricio CHANDIA CABAS, Vernon Johan LOUW, Carmen MARTINEZ CHAMORRO, Gonzalo GARATE, Valeria BUCCHERI, Raimundo GAZITUA PEPPER, Alejandro BERKOVITS, Michael CASS, Eva GONZALEZ BARCA, Jose SANDOVAL-SUS, Muhit OZCAN, Sven Erik OJAVEE, Ima PAYDAR, Mohammed Z.H. FAROOQUI, Ohad BENJAMINI
Institutions: Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, University of Cape Town, Stellenbosch University, Groote Schuur Hospital, Hospital Alemán, Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, Moffitt Cancer Center, Memorial Healthcare System, Ankara University, Merck & Co., Inc., Rahway, NJ, USA (United States), Sheba Medical Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223088532