Pirtobrutinib vs Ibrutinib for CLL/SLL Patients Who Haven’t Had a BTK Inhibitor

During the 2025 American Society of Hematology’s Annual Meeting (ASH) in early December, updates were shared on how pirtobrutinib (Jaypirca, Eli Lilly) compared to ibrutinib (Imbruvica, Johnson&Johnson/Pharmacyclics) as a first treatment for people with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Relapsed means that the CLL/SLL has come back after treatment ends. Refractory means that treatment was not working to control the CLL/SLL. Discover the results and how these findings may shape future care. 

Why compare pirtobrutinib to ibrutinib for CLL/SLL?  

Bruton’s tyrosine kinase (BTK) inhibitors are oral therapies that block signals CLL/SLL cells use to survive and grow. For many years, covalent BTK inhibitors, which permanently bind to the BTK protein, have been a standard option. Ibrutinib is one of the most commonly used medicines in this group.

Pirtobrutinib is different. It is a noncovalent BTK inhibitor, meaning it binds to BTK in a reversible way. This difference may allow it to work even when the BTK protein changes over time. Pirtobrutinib is currently approved for patients who have previously received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. 

In the phase 3 BRUIN-CLL-314 study, researchers evaluated pirtobrutinib as a first treatment and in people with relapsed or refractory CLL/SLL who had not taken a BTK inhibitor before. Earlier research showed that pirtobrutinib worked well in patients who were new to BTK inhibitors. By comparing pirtobrutinib directly with ibrutinib, this study aimed to better understand which BTK inhibitor may be the better option.

There were 662 people enrolled in this study who were randomly assigned to receive pirtobrutinib or ibrutinib. Of those, 225 were treatment naive. This means they were receiving their first treatment for CLL/SLL through the trial. There were 437 people who were relapsed/refractory enrolled in the study. 

Study results: pirtobrutinib proves to be superior to ibrutinib 

When researchers looked at results for all patients, they found that 87% of people taking pirtobrutinib responded to treatment, compared with 78.6% of those taking ibrutinib. They also compared results between people with relapsed/refractory CLL/SLL and people receiving treatment for the first time. For people with relapsed/refractory CLL/SLL, they saw a response rate of 84% for pirtobrutinib versus 74.8% for ibrutinib. Among participants starting treatment for the first time, response rates were high in both groups but again favored pirtobrutinib at 92.9% compared to 85.8% with ibruinib. While follow-up is still ongoing, early data showed a trend toward longer progression-free survival with pirtobrutinib. 

The types of side effects were generally similar between the two BTK inhibitors, but some important differences were seen. Heart problems such as atrial fibrillation occurred less often with pirtobrutinib than ibrutinib. High blood pressure was also less common with pirtobrutinib. Fewer people taking pirtobrutinib needed dose reductions or stopped treatment because their CLL/SLL progressed. These differences matter because certain CLL/SLL treatments like BTK inhibitors are taken for long periods, and better tolerability can help patients stay on therapy longer to limit cancer progression.

Key takeaways

This is the first study to directly compare a noncovalent BTK inhibitor with a covalent one in CLL/SLL. The results show that pirtobrutinib is a better option for both newly diagnosed and relapsed/refractory CLL/SLL than ibrutinib.  

As more follow-up data become available, these findings may help guide future treatment choices. If you’d like to review your eligibility to join this clinical trial, click here. You can also discuss these findings with your CLL/SLL specialist. 

Read this abstract: Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor 

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Sources:

• Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor
• Noninferiority Shown for Pirtobrutinib vs Ibrutinib in CLL/SLL