Pirtobrutinib, an investigational, third-generation Bruton tyrosine kinase (BTK) inhibitor, offered response rates of 60% or higher in most groups of heavily pretreated patients with chronic lymphocytic leukemia (CLL), even those who’ve received other BTK inhibitors as previous treatment, researchers reported in Lancet.

In the phase I and II trial, researchers studied the therapy in 139 patients with CLL or small lymphocytic lymphoma. The overall response rate was 63% across all doses and patient groups, with some of the smaller subsets reporting responses in 52% of patients with mantle cell lymphoma, 68% with Waldenström macroglobulinaemia, and 50% with follicular lymphoma. When divided by prior treatment exposure, pirtobrutinib produced responses in 65% of those with prior BCL2 inhibition, 64% with prior BTK/BCL2 inhibition, 62% with prior BTK inhibition, and 60% with prior PI3K inhibition.

Any-grade adverse events included fatigue (20%), diarrhea (17%), and contusion (13%). Grade 3 or 4 adverse events were neutropenia (10%), anemia (4%), fatigue (1%), and headache (1%), as well as abdominal pain, dyspnea, constipation, and pyrexia each in less than 1% of patients.

Although other BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) are approved for patients with CLL, patients often develop treatment resistance during therapy. Pirtobrutinib binds in a different location and bypasses that resistance, which the researchers said would offer additional potential therapeutic activity and prevent off-target toxicities.