Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
In the first head-to-head comparison of a noncovalent and covalent BTK inhibitor, patients with CLL who were treated with either pirtobrutinib or ibrutinib responded equally well to both treatments.
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Woyach from the Ohio State University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Pirtobrutinib is a non-covalent Bruton tyrosine kinase (BTK) inhibitor used to treat chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) that binds reversibly to BTK. The treatment was originally developed as a way to overcome resistance mutations (C481) that develop with covalent BTK inhibitor treatment (ibrutinib, acalabrutinib, zanubrutinib). Because pirtobrutinib is very selective and safe, and it can inhibit BTK even in the presence of C481 resistance mutations, researchers wanted to know whether it could be more effective than a covalent BTK inhibitor.
Methods and Participants:
BRUIN CLL-314 is a phase 3 randomized clinical trial comparing pirtobrutinib with ibrutinib in previously untreated patients with CLL / SLL as well as patients with relapsed / refractory CLL / SLL. Treatment continued until disease progression or intolerable side effects developed. The primary outcome was overall response rate, which is the percentage of patients whose cancer shrinks or disappears after treatment.
Results:
- A total of 662 patients were randomly assigned to receive either pirtobrutinib or ibrutinib.
- 225 patients were treatment-naïve, and 437 patients had relapsed / refractory CLL.
- Pirtobrutinib was just as effective as ibrutinib (non-inferior), with an overall response rate of 87% compared with 79% for ibrutinib for all patients.
- In treatment-naïve patients, the overall response rate was 93% for pirtobrutinib and 86% for ibrutinib.
- It is still too early for definitive data on progression-free survival outcomes, but the preliminary data favor pirtobrutinib.
Conclusions:
This treatment is the first head-to-head comparison of a noncovalent and covalent BTK inhibitor. Patients with CLL who were treated with either pirtobrutinib or ibrutinib responded equally well to both treatments, whether they had treatment-naïve or relapsed/refractory CLL / SLL. This study, as well as another recent phase 3 clinical trial of pirtobrutinib vs chemoimmunotherapy show that pirtobrutinib is effective as first-line therapy for CLL. However, we are still waiting on long-term follow-up data to see if pirtobrutinib provides any advantage in progression-free survival or overall survival.
There are still concerns that may limit the adoption of pirtobrutinib as a first-line therapy. One of the main concerns with using pirtobrutinib as a first-line therapy is the possibility of developing resistance mutations that would not only lead to relapse but that would also cause covalent BTK inhibitors to be ineffective. We do not yet have data to know whether covalent BTK inhibitors or venetoclax are effective after pirtobrutinib treatment. Another issue is that the comparator groups for these two phase 3 clinical trials (ibrutinib and bendamustine-rituximab) are therapies that are no longer preferred treatment options. Thus, it is difficult to know how pirtobrutinib compares to more contemporary approaches such as acalabrutinib, zanubrutinib, or time-limited combination regimens with venetoclax. Perhaps fortunately, new therapies for CLL have progressed so rapidly with so many good treatment options that it is hard to know how they all compare to each other and how to sequence them, but research is ongoing.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: 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
You can read the full paper here: Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The accompanying editorial can be found here: BRUIN 313 and 314 Trials Open the Door for Noncovalent Bruton Tyrosine Kinase Inhibition as Initial Therapy for Chronic Lymphocytic Leukemia
