Dr. Mato on the Potential Use of Noncovalent BTK Inhibitors in CLL

Anthony Mato, MD, MSCE, hematologic oncologist, director, CLL Program, Memorial Sloan Kettering Cancer Center, discusses recent data on the emerging class of noncovalent BTK inhibitors in chronic lymphocytic leukemia (CLL), and their potential advantage over currently approved covalent BTK inhibitors.

There are currently 3 FDA-approved covalent BTK inhibitors for the treatment of patients with CLL—ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). Although these agents remain effective and viable options, the development and use of noncovalent BTK inhibitors may transform the treatment landscape and become the new standard of care in CLL, Mato begins. 

Treatment discontinuation due to adverse effects [AEs] and resistance mutations are commonly associated with the continuous administration of covalent BTK inhibitors. However, the mechanism of action and high selectivity of noncovalent agents can overcome these limitations while still preventing BTK activity, Mato explains. These agents target and noncovalently bind the target BTK molecule at a different site than covalent molecules, he adds.

Noncovalent BTK inhibitors have shown promising early efficacy and tolerability signals in clinical development, Mato continues. Data on pirtobrutinib (Jaypirca) are the most robust, he states. In the phase 1/2 BRUIN trial (NCT03740529), pirtobrutinib monotherapy was administered to patients with CLL who had previously been treated with BTK inhibitors, Bruin says. Extended follow-up was presented at the 2022 ASH Annual Meeting, and showed that the agent elicited clinically meaningful and durable response rates in this population. Moreover, pirtobrutinib continues to be well-tolerated, with a low rate of AEs and treatment discontinuation, Mato states.

Pirtobrutinib received approval for the treatment of patients with mantle cell lymphoma (MCL), and currently has an FDA orphan drug designation for CLL. Regulatory approval is currently being pursued. Although the agent has not yet been approved in CLL, its future use in clinical practice is highly anticipated, Mato concludes.

Editor’s Note: This interview was conducted prior to the 2022 ASH Annual Meeting.