Next-Generation Bruton's Tyrosine Kinase Inhibition for CLL

Targeting the B-cell receptor pathway with covalent, irreversible inhibitors of Bruton's tyrosine kinase (BTK) is integral to current treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), although resistance often develops due to mutation of C481 in the BTK binding site. Investigators now report an industry-sponsored, multinational, single-arm, phase 1–2 study of the oral, noncovalent, reversible BTK inhibitor pirtobrutinib in 317 patients with relapsed or refractory CLL/SLL.

Among the 247 patients who had previously received a covalent BTK inhibitor, the median number of prior lines of therapy was 3 (range, 1–11); 41% had also received a B-cell lymphoma 2 (BCL2) inhibitor, and most had also received an anti-CD20 monoclonal antibody (88%) and chemotherapy (79%). The overall response rate (primary endpoint) with pirtobrutinib was 73.3%; almost all responses were partial. The median progression-free survival was 19.6 months. Responses were similar in the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor.

Among all 317 patients, only 2.8% discontinued pirtobrutinib due to an adverse event; the most common grade 3 or higher adverse events were infection and neutropenia (28% and 27% of patients, respectively).