Syed Ibrahim, Nghia Pham, Aarushi Sahni, Samantha Sekeres, Allison Cool, Justin Taylor, Catherine C. Coombs
Pirtobrutinib, a novel noncovalent Bruton's tyrosine kinase (BTK) inhibitor (BTKi) has demonstrated significant potential in overcoming treatment resistance characterized by BTK mutations in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL). Unlike currently approved covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib that irreversibly bind to the cysteine 481 (C481) residue of BTK, pirtobrutinib's non-covalent binding enables it to maintain efficacy even in the presence of cysteine 481 serine (C481S) mutations which are the most common form of acquired resistance. This current review seeks to demonstrate the mechanism of action as well as the clinical efficacy of pirtobrutinib in treating patients with relapsed/refractory CLL/SLL and to describe ongoing studies of pirtobrutinib in combination with other agents and in earlier lines of therapy.