Abstract Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton’s Tyrosine Kinase (BTK) and C481S mutant BTK. We evaluated safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenstrom’s macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase 1 MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 mg to 75 mg once-daily in 28-day cycles. Dose finding progressed using a 3+3 dose escalation design. Primary endpoints were safety and the recommended phase 2 dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11 [23.4%]), febrile neutropenia (7 [14.9%]), and pneumonia (7 [14.9%]). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily.