Pirtobrutinib, a non-covalent Bruton tyrosine kinase (BTK) inhibitor, has demonstrated non-inferiority to ibrutinib, a covalent BTK inhibitor, in overall response rate among patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This conclusion comes from the first phase III clinical trial directly comparing these two types of BTK inhibitors.
The study included 662 adult patients diagnosed with CLL or SLL. Among them, 225 had not received prior treatments, while 437 were either relapsed or refractory to previous therapies but had not been treated with any BTK inhibitors. Participants were randomly assigned to receive either pirtobrutinib or ibrutinib and continued treatment unless their disease progressed or side effects became unacceptable.
Lead study author Jennifer Woyach, MD, Bertha Bouroncle, MD, and Andrew Pereny, chair of medicine at The Ohio State University College of Medicine said: "Pirtobrutinib was clearly non-inferior to ibrutinib, and the response rate actually favors pirtobrutinib in the total cohort. This shows that pirtobrutinib is a reasonable choice in both the treatment-naive and relapsed/refractory settings."
CLL and SLL are slow-growing forms of non-Hodgkin lymphoma caused by uncontrolled growth of lymphocytes. BTK inhibitors target the enzyme responsible for B-cell proliferation.
In terms of overall response rate (ORR), pirtobrutinib achieved an ORR of 87.0% compared to 78.6% for ibrutinib across all participants. The advantage for pirtobrutinib was observed consistently among various subgroups including those newly diagnosed as well as those with high-risk disease characteristics.
Progression-free survival will be formally evaluated later; however, early findings indicate potential benefits for pirtobrutinib with an estimated 18-month progression-free survival rate of 86.9%, compared to 82.3% for the group receiving ibrutinib. The benefit appeared most pronounced among participants who had not previously undergone treatment.
Both drugs showed similar rates of adverse events and discontinuations due to side effects. However, patients on pirtobrutinib experienced fewer dose reductions related to adverse events and lower rates of certain cardiovascular issues such as hypertension and atrial fibrillation.
Dr. Woyach commented: "While the efficacy and safety of pirtobrutinib have been very clearly established when given after a covalent BTK inhibitor, there are likely going to be subgroups of patients where pirtobrutinib is a more attractive option instead of the covalent BTK inhibitors."
She also noted ongoing research efforts: future trials may help determine optimal uses for pirtobrutinib alone or in combination with other therapies as initial treatment options. Investigations into resistance mechanisms against non-covalent BTK inhibitors are underway.
The study received funding from Eli Lilly and Company—the manufacturer of pirtobrutinib—and results were published simultaneously in the Journal of Clinical Oncology.
Jennifer Woyach will present further details on December 7 at the Orange County Convention Center.
