Pirtobrutinib is being investigated in clinical trials in patients with CLL/small lymphocytic lymphoma, mantle cell lymphoma and non-Hodgkin’s lymphoma.
Pirtobrutinib (L0X0-305) is a highly selective inhibitor used to treat patients with chronic lymphocytic leukemia (CLL).1 While there are several other drugs in the same class of Bruton’s tyrosine kinase (BTK) inhibitors, they each have different characteristics and pharmacological properties.2
Of particular note, pirtobrutinib is the first to offer the hallmark of non-covalent, reversible binding. This will allow for higher BTK inhibition and higher selectivity, reducing any unwanted side effects.
There is growing concern about the development of resistance to covalent BTK inhibitors, leading to treatment discontinuation in a large majority of patients. Researchers recognize pirtobrutinib for its ability to treat recurrent or recurrent CLL.
Mechanism of action
B cell malignancies often develop as a result of signaling during the B cell receptor pathway. BTK is a protein found early in this pathway. Inhibitors target it for therapeutic intervention to downregulate signaling and cell growth.
Ibrutinib is one of several discovered BTK inhibitors that treat a range of B-cell lymphomas. However, patients with B cell malignancies often develop resistance to BTK inhibitors during therapy. Mutations at the Cys-481 residue confer resistance to first and second generation BTK inhibitors.3
As a third generation BTK inhibitor, pirtobrutinib is not dependent on binding to Cys-481 in the active site, therefore no resistance occurs. As the body synthesizes new amounts of BTK, pirtobrutinib stays in the body and causes constant inhibition. This is in contrast to other BTK inhibitors, which do not have long half-lives and cause inhibition gaps.
Currently, pirtobrutinib is being investigated in clinical trials in patients with CLL/small lymphocytic lymphoma, mantle cell lymphoma and non-Hodgkin’s lymphoma. The BROWN phase 1/2 study has shown that patients tolerate pirtobrutinib well. Of the 252 patients with CLL/SLL in the study, the overall response rate was a promising 68%.4
Side Effects (AEs)
Researchers have not yet determined a maximum tolerated dose. Phase 2 of the BROWN study aims to determine the therapeutic range. Only 1% of patients permanently discontinued pirtobrutinib due to treatment-related adverse events.4 The most common adverse reactions were diarrhoea, fatigue and neutropenia, with rare cases of bleeding and hypertension.
Multiple studies around the world are evaluating the safety and efficacy of pirtobrutinib. Researchers at Loxo Oncology at Lilly are currently enrolling participants in phases 2 and 3 of the BROWN trial.
Pirtobrutinib shows promise for the treatment of relapsing and relapsing CLL.
About the author
Greta Staubly is a 2024 PharmD candidate at the University of Connecticut.
- Overview BTK Inhibitor Molecule | Loxo Oncology. Lillyloxooncologypipeline.com. https://www.lillyloxooncologypipeline.com/molecule/btk-inhibitor?gclid=CjwKCAjwv-GUBhAzEiwASUMm4rr69kaDRjX_VR-HBgVo6TGVW2OwrVw3S1Nvuh9EXFoB6Jjd87XUnhoCh5BwE. Published 2022. Accessed June 1, 2022.
- Shirley M. Bruton Tyrosine Kinase Inhibitors in B Cell Malignancies: Their Uses and Differential Characteristics [published correction appears in Target Oncol. 2021 Dec 24;:]. target Oncol. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8
- Mato A. Rapid readout: Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in treatment-experienced CLL/SLL: updated results from the phase 1/2 BROWN trial. OncLive. https://www.onclive.com/view/pirtobrutinib-a-highly-selective-non-covalent-reversible-btk-inhibitor-in-previously-treatment-cll-sll-updated-results-from-the-phase- 1-2 brown study. Published 2022. Accessed June 1, 2022.
- Expanded Access Program for Pirtobrutinib for Participants with B Cell Cancer – Full Text View – ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT05172700. Published 2022. Accessed June 1, 2022.