A new phase I/II clinical trial has demonstrated promising results for pirtobrutinib, a highly selective non-covalent Bruton tyrosine kinase inhibitor (BTKi), in patients with B-cell malignancies who were previously intolerant to covalent BTKi therapy. The BRUIN study, published in January 2025 in the journal Haematologica, evaluated the safety and efficacy of pirtobrutinib monotherapy in patients who had discontinued prior BTKi treatment due to adverse events.
The multi-center, open-label BRUIN trial was conducted across multiple sites internationally and funded by Loxo Oncology, a subsidiary of Eli Lilly and Company. The study enrolled 127 patients with various B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and other non-Hodgkin lymphomas, who had previously discontinued at least one BTKi therapy due to intolerance.
Patients were eligible for inclusion if they had relapsed or refractory B-cell malignancies and had discontinued prior BTKi therapy due to persistent or recurrent adverse events in the absence of disease progression. The study allowed enrollment of patients with ongoing anticoagulation/antiplatelet treatment and those with controlled atrial fibrillation. The median age of participants was 70 years, with a range of 42-87 years.
The primary objectives of the study were to assess the safety and tolerability of pirtobrutinib in this patient population, as well as to evaluate its efficacy. Patients received pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles, with the recommended phase II dose established at 200 mg once daily.
Results showed that pirtobrutinib was generally well-tolerated in patients previously intolerant to covalent BTKis. The most common treatment-emergent adverse events (TEAEs) were fatigue (39.4%) and neutropenia (37.0%). Importantly, the recurrence of adverse events that had previously led to discontinuation of prior BTKi therapy was relatively low with pirtobrutinib treatment. For instance, among 40 patients who had discontinued prior BTKi due to cardiac disorders, only 25% experienced recurrence of any cardiac event with pirtobrutinib.
Efficacy data were particularly encouraging for patients with CLL/SLL and MCL. In 78 CLL/SLL patients, the overall response rate (ORR) to pirtobrutinib was 76.9%, while 21 MCL patients achieved an ORR of 81.0%. The median progression-free survival for CLL/SLL patients was 28.4 months, while it was not yet reached for MCL patients at the time of analysis.
One of the key findings of the study was that no patient discontinued pirtobrutinib due to the same adverse event that had led to discontinuation of their prior BTKi therapy. This suggests that pirtobrutinib may offer a viable treatment option for patients who have experienced intolerance to covalent BTKis, potentially allowing for continued BTK inhibition in these individuals.
The study does have some limitations that should be considered when interpreting the results. As an exploratory subgroup analysis from a single-arm study, it lacks a direct comparison to other treatments or a control group. Additionally, detailed data on the severity of adverse events leading to discontinuation of prior BTKi therapy were not available, limiting the ability to make direct comparisons of tolerability between prior treatments and pirtobrutinib.
The authors concluded that pirtobrutinib demonstrated a favorable safety profile and promising efficacy in patients with prior BTKi intolerance. They suggest that pirtobrutinib may be an important option to extend the benefit of BTK inhibition among patients who discontinued prior BTKi therapy due to intolerance rather than disease progression.
The potential clinical impact of these findings is significant. For patients with B-cell malignancies who have had to discontinue covalent BTKi therapy due to intolerance, pirtobrutinib may offer a new treatment option that allows for continued targeting of the BTK pathway. This could be particularly valuable in diseases like CLL/SLL, where maintaining BTK inhibition is often crucial for long-term disease control.
Furthermore, the ability to switch to pirtobrutinib after covalent BTKi intolerance may delay the need to transition to other drug classes, such as BCL-2 inhibitors, which can require more intensive monitoring and management. This could potentially simplify treatment regimens and improve quality of life for some patients.
While these results are promising, further research will be needed to confirm the long-term safety and efficacy of pirtobrutinib in larger patient populations and in comparison to other treatment options. Additionally, studies examining the use of pirtobrutinib in earlier lines of therapy or in combination with other agents may further elucidate its role in the treatment landscape for B-cell malignancies.
As the field of targeted therapies for hematologic malignancies continues to evolve, pirtobrutinib represents an important addition to the armamentarium, potentially offering a solution for patients who have struggled with intolerance to previous BTK inhibitors. Ongoing and future studies will help to define its optimal place in treatment algorithms and its impact on long-term outcomes for patients with B-cell malignancies.
References
Shah NN, Wang M, Roeker LE, et al. Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial. Haematologica. 2025;110(1):92-102. Published 2025 Jan 1. doi:10.3324/haematol.2024.285754
