Jaypirca shows promise as a frontline treatment for CLL/SLL patients | ASH 2025

The results of a new study suggest that Jaypirca (pirtobrutinib) might be a good option for some patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In a head-to-head comparison, Jaypirca met the endpoint of non-inferiority to Imbruvica (ibrutinib) for patients who are treatment-naïve and for those who have relapsed/refractory disease, according to data presented today at the 67th American Society of Hematology (ASH) Annual Meeting being held in Orlando.

Chronic lymphocytic leukemia and small lymphocytic lymphoma 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). The American Cancer Society estimates that in 2025, about 80,350 people will be diagnosed with non-Hodgkin lymphoma, and about 19,390 people will die from this cancer.

Targeted therapies, including inhibitors of the Bruton tyrosine kinase (BTK), have replaced chemotherapy as frontline treatment because of better outcomes. Covalent BTK inhibitors, such as Imbruvica, form a strong and permanent bond with Bruton tyrosine kinase. This bond blocks BTK’s signaling function, stopping malignant B-cells from growing and surviving. Developed by Johnson & Johnson, Imbruvica is currently approved to treat both chronic lymphocytic leukemia and small lymphocytic lymphoma, as well as graft-versus-host disease and Waldenström’s macroglobulinemia.

“Although covalent BTK inhibitors have transformed the therapeutic landscape for patients with CLL and SLL, pharmacologic limitations may ultimately compromise their efficacy,” Jennifer A. Woyach, M.D., professor in the College of Medicine and co-leader of the Leukemia and Hematologic Malignancies Program at The Ohio State University, said during a press briefing.

Resistance often develops with the use of covalent BTK inhibitors, and patients need to be monitored for treatment-related effects, such as bleeding, infections, and cardiac-related issues including arrhythmias, cardiac failure and sudden death, as well as liver injury.

“Pirtobrutinib is a highly selective non-covalent BTK inhibitor that was initially designed to overcome the resistance to covalent BTK inhibitors,” Woyach said. “Due to the potent inhibition of BTK and the safety of the molecule, we hypothesized that there may be improved efficacy as well as tolerability of pirtobrutinib compared with covalent BTK inhibitors.”

Non-covalent BTK inhibitors create a temporary bond, are reversible and have fewer side effects. Developed by Eli Lilly, Jaypirca was recently granted full approval for adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who have previously been treated with a covalent BTK inhibitor. Previously, it was available under an accelerated approval. Jaypirca is also approved to treat adults with relapsed or refractory mantle cell lymphoma.

Woyach and her colleagues wanted to compare Jaypirca and Imbruvica in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma in the first study that directly compares a non-covalent BTK inhibitor to a covalent BTK inhibitor.

In this phase 3 clinical trial, investigators enrolled 662 adult patients with CLL or SLL. Of these, 225 had not received any prior treatments, and 437 were relapsed or refractory to prior treatments and had not received any BTK inhibitors.

The study’s primary endpoint, non-inferiority of Jaypirca for overall response rate (ORR), was achieved in the full study population. Of 662 participants, the overall response rate was 87.0% among those receiving Jaypirca and 78.6% among those receiving Imbruvica.

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

The rates of treatment-emergent adverse events (AEs) and treatment discontinuation due to AEs were overall similar between arms. However, those receiving Jaypirca 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.

Researchers said future studies could help refine the use of Jaypirca alone or in combination with other therapies as a frontline treatment. She added that they are also continuing to investigate possible mechanisms through which cancer may become resistant to non-covalent BTK inhibitors.

The study was sponsored by Lilly.