Evolution of BTK inhibitors

The purpose of this clinical review evaluates the evolution of bruton’s tyrosine kinase (BTK) inhibitors in becoming the standard of care in treating chronic lymphocytic leukemia (CLL). The first-generation BTK inhibitor ibrutinib has demonstrated superior efficacy over traditional chemotherapy in several randomized clinical trials in terms of progression free survival (PFS). However, due to cardiovascular toxicities of atrial fibrillation (afib), hypertension (HTN), and bleeding, have led to drug discontinuation. Second-generation BTK inhibitors, acalabrutinib and zanubrutinib have demonstrated reduced rates in cardiovascular toxicities due to improved BTK receptor selectivity, as seen in three head-to-head ibrutinib clinical trials. The emergence of BTK mutation C481S had led to the creation of noncovalent or reversible BTK inhibitors, such as pirtobrutinib. Clinicians need to be able to understand when and how to order testing that proves a patient has developed BTK resistance. The emergence of another mutation, that is not related to C481S, called non-C481S is of clinical interest. BTK protein degraders are in clinical development to test against C481 and non-C481 mutations.