The Bottom Line:
Pirtobrutinib was generally well-tolerated, and most patients did not experience high-grade recurrence of the adverse event that led to discontinuation of the prior covalent Bruton tyrosine kinase inhibitor (BTKi). Pirtobrutinib may be an important option to extend the benefit of BTK inhibition among patients who could not tolerate previous covalent BTKi treatment.
Who Performed the Research and Where Was it Presented:
Dr. Nirav Shah from the Medical College of Wisconsin and colleagues presented the results at the American Society for Hematology Annual Meeting in 2022.
BTKi has been wonderfully effective for managing chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, ibrutinib, the first approved BTKi, has several off-target effects, including abnormal heart rhythms, high blood pressure, bleeding, and bruising, making it difficult to tolerate. Most patients who stop taking ibrutinib do so because of the side effects, not a progressive disease. While acalabrutinib and zanubrutinib are more specific and don’t cause as many side effects, they still belong to the same class of drugs known as covalent (irreversible) BTKi.
In this interview, our own Dr. Brian Koffman interviewed Dr. Nirav Shah, Associate Professor of Medicine at the Medical College of Wisconsin, focusing on hematological malignancies. They discussed results from a clinical trial of pirtobrutinib, a new reversible Bruton tyrosine kinase (BTK) inhibitor. Pirtobrutinib is a highly selective, non-covalent (reversible) BTK inhibitor, which inhibits both wildtype and C481-mutant BTK.
One of the significant advantages of pirtobrutinib over the three approved irreversible BTK inhibitors is that it will work for many patients who develop resistance to those other drugs due to its different binding modes.
This study investigates a different possible advantage, namely how well pirtobrutinib is tolerated in patients who can no longer take one of the three approved BTKi.
Methods and Participants:
The BRUIN study is a phase 1/2 clinical trial testing pirtobrutinib in patients with previously treated B-cell malignancies, including those with CLL/SLL. This analysis looked at patients with documented intolerance to a prior covalent BTK inhibitor, meaning they discontinued treatment due to recurrent/persistent adverse events and not a progressive disease.
- A total of 123 patients out of 566 enrolled in the BRUIN study had discontinued a prior BTKi due to adverse events (79 were CLL/SLL patients).
- Patients in this cohort had received one or more of the following therapies: ibrutinib (n=118, 96%), acalabrutinib (n=29, 24%), or zanubrutinib (n=6, 5%).
- Most patients (68%) were able to stay on pirtobrutinib.
- 45 patients discontinued pirtobrutinib, and of those patients, most discontinued because of progressive disease (62%)
- Approximately 7% of patients discontinued pirtobrutinib due to an adverse event, which included low white blood cell count, COVID-19 infection, muscle pain, and rash.
- Overall recurrence of a severe (grade ≥3) pirtobrutinib-related adverse event in the same patient and category as that leading to prior covalent BTKi discontinuation was observed in only 13% (n=16/123) of patients.
No matter how effective a drug is, if you can’t tolerate it, you will not take it. In this study, pirtobrutinib was generally well-tolerated, and most patients did not experience high-grade recurrence of the adverse event that led to discontinuation of the prior covalent BTKi. Pirtobrutinib may be an important option to extend the benefit of BTK inhibition among patients who could not tolerate previous BTKi.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Safety and Tolerability of Pirtobrutinib Monotherapy in Patients with B-Cell Malignancies Who Were Previously Intolerant to a Covalent BTK Inhibitor: Results from the Phase 1/2 BRUIN Study
Take care of yourself first.
Ann Liu, PhD