Dr O’Brien on the Potential Role for Noncovalent BTK Inhibitors in MCL and CLL

Susan M. O’Brien, MD, associate director, clinical science, Chao Family Comprehensive Cancer Center, medical director, Sue and Ralph Stern Center for Clinical Trials and Research, University of California, Irvine (UCI), professor, Division of Hematology/Oncology, Medicine, UCI School of Medicine, discusses the potential role for noncovalent BTK inhibitors in the treatment of patients with mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).

Covalent BTK inhibitors, such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), have an established role in the treatment paradigm for MCL and CLL. However, noncovalent BTK inhibitors, such as pirtobrutinib (Jaypirca), could represent key treatment options for patients with MCL who experience disease progression following treatment with a covalent BTK inhibitor, or for patients with CLL who progress following a covalent BTK inhibitor and venetoclax (Venclexta), O’Brien says.

In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory MCL following at least 2 lines of systemic therapy, including a BTK inhibitor. This was based on data from the single-arm phase 1/2 BRUIN trial (NCT03740529), which showed that pirtobrutinib elicited an overall response rate of 50% in this patient population. Notably, in findings from the study among patients with CLL or small lymphocytic lymphoma, pirtobrutinib produced an ORR of 73.3%, and the hope is to eventually see this agent approved in the CLL space, O’Brien continues.

As covalent BTK inhibitors are utilized more frequently in the treatment of patients with MCL or CLL, patients will continue to develop resistance, O’Brien emphasizes, adding that when a patient develops resistance to 1 covalent BTK inhibitor, switching to another is not an option. Specifically, within the CLL space, patients who progress following a covalent BTK inhibitor and venetoclax have no current standard-of-care treatment, and there remains a need for a preferred therapy for these patients, she continues.

The populations of patients with MCL or CLL who have experienced disease progression after a covalent BTK inhibitor will continue to increase over time as these small molecules are used more frequently, underscoring the need for additional agents in later lines of treatment, O’Brien concludes.