Pirtobrutinib: A New Selective BTK Inhibitor Under Study in MCL

By: Amy MacDonald, MS
Posted: Friday, February 21, 2025

Madeline D. Schultze, PharmD, and David J. Reeves, PharmD, BCOP, both of Butler University, Indianapolis, conducted a literature review of available data on the efficacy and safety of pirtobrutinib, a novel small-molecule Bruton’s tyrosine kinase (BTK) inhibitor, in the treatment of mantle cell lymphoma (MCL). Their review, published in the Annals of Pharmacotherapy, found that pirtobrutinib has a similar safety profile to older (covalent) BTK inhibitors. However, they noted, pirtobrutinib was able to retain activity in patients experiencing BTK receptor mutations attributable to previous treatment with the first-generation BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib.

“Pirtobrutinib’s unique noncovalent, reversible mechanism of action and high selectivity for BTK allow for the potential to overcome previous BTK inhibitor resistance and may create a superior safety profile,” the authors noted.

Of note, the review described data from the first phase I/II human clinical trial (BRUIN). This trial evaluated pirtobrutinib in 323 adults with B-cell malignancies who had received prior treatment. Seven dose levels of pirtobrutinib (25–300 mg) were assessed. No dose-limiting toxicities were observed, a maximum tolerated dose was not established, and a phase II dose of 200 mg of pirtobrutinib was selected.

In May 2023, an efficacy update was published for the 164 patients from BRUIN with MCL (90 of whom had received a prior BTK inhibitor). After a median follow-up of 12 months, those receiving a prior BTK inhibitor had an overall response rate of 58% (complete response rate = 20%), median progression-free survival of 7.4 months (95% confidence interval = 5.3–12.5 months), and an overall survival rate at 12 months of 68%. Atrial fibrillation, a class effect observed with BTK inhibitors, however, appeared to be less common with pirtobrutinib than previous-generation drugs in this population.

Trials are ongoing to confirm the results of the BRUIN trial and to potentially expand the use of pirtobrutinib in MCL.

Disclosure: The study authors reported no conflicts of interest.

Annals of Pharmacotherapy

---