Evidence grows for pirtobrutinib as a safer and effective alternative for CLL and SLL

Pirtobrutinib, a non-covalent Bruton tyrosine kinase (BTK) inhibitor, met the primary endpoint for non-inferiority in terms of overall response rate in the first head-to-head comparison with ibrutinib, a covalent BTK inhibitor. Based on the study results, researchers suggest pirtobrutinib shows promise as initial BTK inhibitor therapy, including in the frontline setting, for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

Non-covalent BTK inhibitors were initially developed to overcome resistance to covalent BTK inhibitors. This study is the first phase III clinical trial to directly compare a non-covalent BTK inhibitor to a covalent BTK inhibitor in patients with CLL or SLL. It included patients who had not received any previous treatment, a first for any phase III study directly comparing BTK inhibitors, as well as patients who had their cancer come back (relapse) or not respond (refractory) after receiving treatments other than a covalent BTK inhibitor.

"Pirtobrutinib was clearly non-inferior to ibrutinib, and the response rate actually favors pirtobrutinib in the total cohort," said lead study author Jennifer Woyach, MD, Bertha Bouroncle, MD, and Andrew Pereny, chair of medicine at The Ohio State University College of Medicine. "This shows that pirtobrutinib is a reasonable choice in both the treatment-naive and relapsed/refractory settings."

lead study author Jennifer Woyach, MD, Bertha Bouroncle, MD, and Andrew Pereny, chair of medicine at The Ohio State University College of Medicine

CLL and SLL are slow-growing forms of non-Hodgkin lymphoma that develop when lymphocytes grow out of control and abnormal B cells build up in bone marrow (CLL) or lymph nodes (SLL). BTK inhibitors work by blocking the BTK enzyme, which plays a role in B-cell growth and proliferation.

The study enrolled 662 adult patients with CLL or SLL. Of these, 225 had not received any prior treatments, and 437 were R/R to prior treatments and had not received any BTK inhibitors. Participants were randomly assigned to receive either pirtobrutinib or ibrutinib and remain on their assigned therapy unless their disease progressed or they experienced unacceptable side effects.

The study's primary endpoint, non-inferiority of pirtobrutinib for overall response rate (ORR), was achieved in the full study population. Of 662 participants, the ORR was 87.0% among those receiving pirtobrutinib and 78.6% among those receiving ibrutinib. The results consistently favored pirtobrutinib across the majority of subgroups, including those who were treatment-naive, relapsed/refractory (R/R) to prior treatments, and those with various high-risk disease characteristics.

Survival without disease progression, the study's secondary endpoint, will be formally assessed at a later time. Early results suggest that pirtobrutinib may offer some benefit over ibrutinib for this endpoint as well, showing 18-month progression-free survival (PFS) rates of 86.9% in the pirtobrutinib arm and 82.3% in the ibrutinib arm. Preliminary results suggest treatment-naive participants saw the most pronounced benefit for this endpoint.

The PFS is still a little bit immature at this point, but trends toward favoring pirtobrutinib in all of the groups – in the total cohort, in the R/R group, and, importantly, in the treatment-naive cohort. That's really important, because given the safety of pirtobrutinib, it suggests that this might be a good option in the future for some patients with frontline CLL/SLL."

Dr. Jennifer Woyach, The Ohio State University College of Medicine

The rates of treatment-emergent adverse events (AEs) and treatment discontinuation due to AEs were overall similar between arms. However, those receiving pirtobrutinib experienced lower rates of AE-related dose reductions, treatment discontinuation due to progressive disease, and certain cardiovascular AEs including hypertension and development of atrial fibrillation or flutter.

These results may indicate pirtobrutinib is especially suitable for use in older or more frail patients. "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," said Dr. Woyach.

In addition to continuing to track outcomes from this study, Dr. Woyach said that future clinical trials could help refine the use of pirtobrutinib alone or in combination with other therapies as a frontline treatment. She added that researchers are also continuing to investigate possible mechanisms through which cancer may become resistant to non-covalent BTK inhibitors to further optimize treatment strategies.

This study was funded by Eli Lilly and Company, maker of pirtobrutinib. The results were simultaneously published in the Journal of Clinical Oncology.

Jennifer Woyach, MD, of The Ohio State University College of Medicine, will present this study on Sunday, December 7, 2025, at 5:30 p.m. Eastern time in W224ABEF of the Orange County Convention Center.