Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study

Background: The majority of patients (pts) discontinue covalent (c) Bruton tyrosine kinase (BTK) inhibitors (BTKi) for either progression or intolerance. BTK Cysteine 481 substitution is known to contribute to cBTKi acquired resistance to ibrutinib, acalabrutinib, and zanubrutinib.Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib has demonstrated broad efficacy in pts with chronic lymphocytic leukemia (CLL) following prior therapy, including those treated with a prior cBTKi, independent of BTK C481 mutational status (Mato et al, NEJM, 2023). Here we report the largest systematic evaluation of genomic evolution in pts with CLL treated with pirtobrutinib conducted to date, using a larger cohort of pts and longer follow-up than previously reported.