Supplementary Figure S1 shows mean (+SD) plasma concentrations of nemtabrutinib vs time following single (C1D1) oral doses of MK-1026 (linear and semi-log plots) nM

Abstract Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the 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 Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 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 II 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. Significance: This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5

Introduction: Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, resistance to BTKi develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. MK-1026 (formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481- mutated BTK. In the phase 1/2 dose escalation and dose expansion study NCT03162536, the preliminary recommended phase 2 dose (RP2D) of MK-1026 was determined to be 65 mg once daily. The efficacy and safety of MK-1026 in participants with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose expansion phase.