The potential of pirtobrutinib in multiple B-cell malignancies

Bruton’s tyrosine kinase represents a crucial signaling component that operates downstream of the B-cell receptor, and its inhibition has proven to be an effective strategy in treating B-cell cancers. This inhibition has been achieved through the use of irreversible, covalent inhibitors such as ibrutinib and acalabrutinib.

All covalent BTK inhibitors that have received approval from regulatory authorities depend on their ability to bind to the cysteine 481 amino acid located within the active site of BTK, thereby inactivating the enzyme. While these covalent BTK inhibitors have demonstrated significant success in treating various B-cell malignancies, leading to improvements in both overall survival and progression-free survival compared to chemoimmunotherapy in phase 3 clinical trials, their use can be associated with issues of tolerability and the eventual progression of the disease.

Pirtobrutinib represents a new class of BTK inhibitors; it is highly selective and non-covalent, meaning it binds to BTK in a way that does not depend on cysteine 481. A recent phase 1/2 clinical trial conducted as the first study in humans showed that pirtobrutinib was exceptionally well tolerated and resulted in disease remission in patients with multiple B-cell malignancies whose disease had relapsed or was refractory to previous treatments.

This review examines the pharmacological reasoning behind the development of non-covalent BTK inhibitors, the clinical necessity for such inhibitors, the available data on the safety profile of pirtobrutinib and the mechanisms by which resistance to it might arise, and the upcoming clinical trials designed to determine the clinical usefulness of pirtobrutinib. This novel inhibitor has the potential to address several unmet clinical needs for individuals suffering from B-cell malignancies.