Oncology Overview: Pirtobrutinib—A New BTK Inhibitor

Pirtobrutinib (L0X0-305) is a highly selective inhibitor used to treat patients with chronic lymphocytic leukemia (CLL).¹ Although there are various other drugs in the same class of Bruton’s tyrosine kinase (BTK) inhibitors, each possesses different characteristics and pharmacological properties.²

Of particular interest, pirtobrutinib is the first to offer the characteristic of non-covalent, reversible binding. This will allow higher BTK inhibition and a higher selectivity, reducing any off-target adverse effects.

There is growing concern for the development of resistance to covalent BTK inhibitors, leading to treatment discontinuation in a large majority of patients. Researchers are recognizing pirtobrutinib for its ability to treat recurrent or relapsing CLL.

Mechanism of Action

B-cell malignancies often develop due to 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 numerous BTK inhibitors discovered that treat a range of B-cell lymphomas. However, patients with B-cell malignancies often acquire resistance to BTK inhibitors during therapy. Mutations at the Cys-481 residue cause resistance against first and second generation BTK inhibitors.³

As a third generation BTK inhibitor, pirtobrutinib does not rely on binding to Cys-481 in the active site, therefore resistance does not occur. As the body synthesizes new amounts of BTK, pirtobrutinib will remain in the body and cause constant inhibition. This is unlike other BTK inhibitors, which do not have long half-lives and cause gaps in inhibition.

Clinical Development

Currently, pirtobrutinib is under investigation in clinical trials in patients with CLL/small lymphocytic lymphoma, mantle cell lymphoma, and non-Hodgkin lymphoma. The BRUIN phase 1/2 trial has shown that patients tolerate pirtobrutinib well. Of 252 patients with CLL/SLL in the trial, the overall response rate was a promising 68%.⁴

Adverse Events (AEs)

Researchers have not yet determined a maximum tolerated dose. Phase 2 of the BRUIN trial aims to determine the therapeutic range. Only 1% of patients permanently discontinued pirtobrutinib because of treatment-related AEs.⁴ The most common AEs included diarrhea, fatigue, and neutropenia, with hemorrhage and hypertension occurring in rare cases.

Multiple studies throughout the world are evaluating pirtobrutinib’s safety and efficacy. Researchers at Loxo Oncology at Lilly are currently enrolling participants in phases 2 and 3 of the BRUIN trial.

Pirtobrutinib shows promise for treating recurrent and relapsing CLL.

About the Author

Greta Staubly is a 2024 PharmD candidate at the University of Connecticut.

References

1. BTK Inhibitor Molecule Overview | Loxo Oncology. Lillyloxooncologypipeline.com. https://www.lillyloxooncologypipeline.com/molecule/btk-inhibitor?gclid=CjwKCAjwv-GUBhAzEiwASUMm4rr69kaDRjX_VR-HBgVo6TGVW2OwrVw3S1Nvuh9EXFoB6Jjd87XUnhoCh5QQAvD_BwE. Published 2022. Accessed June 1, 2022.
2. Shirley M. Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features [published correction appears in Target Oncol. 2021 Dec 24;:]. Target Oncol. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8
3. Mato A. Rapid Readout: Pirtobrutinib, A Highly Selective, Noncovalent (Reversible) BTK Inhibitor In Previously Treated CLL/SLL: Updated Results From The Phase 1/2 BRUIN Study. OncLive. https://www.onclive.com/view/pirtobrutinib-a-highly-selective-non-covalent-reversible-btk-inhibitor-in-previously-treated-cll-sll-updated-results-from-the-phase-1-2-bruin-study. Published 2022. Accessed June 1, 2022.
4. 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.