Phase 2 nemtabrutinib reversible non-covalent BTK inhibitor + venetoclax BCL-2 inhibitor in frontline CLL/SLL.

This Phase 2, single-arm frontline study evaluates an all-oral combination of nemtabrutinib (MK-1026)—a reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor that can inhibit wild-type BTK and some BTK pathway mutants—and venetoclax (AbbVie/Genentech), a selective BCL-2 inhibitor that promotes apoptosis in CLL cells. Patients with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma receive nemtabrutinib daily in 28-day cycles, with venetoclax added starting cycle 3, for up to 14 cycles; serial CT imaging, marrow assessments, and blood sampling support response and correlative endpoints. A key scientific angle is whether pairing Merck’s next-generation BTK inhibitor with fixed-duration venetoclax can drive deeper remissions, including undetectable MRD at a very sensitive 10^-6 threshold by clonoSEQ after 14 cycles. Today’s frontline CLL care is typically continuous BTK inhibition (e.g., ibrutinib/acalabrutinib/zanubrutinib) or time-limited venetoclax plus an anti-CD20 antibody, and this explores a chemotherapy-free, BTK+ BCL-2 doublet that could be both time-limited and highly MRD-directed.