Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have transformed the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma. Still, CLL/SLL is smart and can mutate to try to escape treatment. The most common way this happens is by a mutation in the drug’s binding site at C481, preventing those first-generation BTK inhibitors from irreversibly binding to and blocking BTK, rendering those drugs largely ineffective.
Pirtobrutunib (formerly LOXO-305) is a reversible (non-covalent) BTK inhibitor. This means that it binds specifically to BTK, but it binds at a different site and in a different way than irreversible (covalent) BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib. Pirtobrutinib does not seem to be affected by changes in the C481 binding site. It remains able to turn off BTK when the irreversible binders are no longer effective.
At the American Society of Hematology (ASH) 2021, Dr. Deborah Stephens, a CLL specialist at the University of Utah Huntsman Cancer Institute, interviewed Dr. Anthony Mato, Director of the CLL program at Memorial Sloan Kettering Cancer Center in New York. They discussed updated results from the BRUIN study, a phase 1/2 clinical trial of pirtobrutinib in patients with advanced B-cell malignancies, including CLL, who have received >2 prior therapies.
- Last year, Dr. Mato presented data from the BRUIN study at the 2020 ASH meeting, and our previous coverage can be found here.
- This year he presented updated results with more patients, longer follow-up times, and more patients with BTK resistance mutations.
- 323 patients with B-cell malignancies were enrolled in the trial, including 170 patients with CLL/SLL.
- 86% of CLL/SLL patients had previously been treated with a BTK inhibitor.
- The overall response rate (ORR) was 63% among all patients.
- Among patients who have previously discontinued a BTKi due to progression, the ORR was 68%.
- Responses deepened over time, with an ORR of 86% among the patients with at least ten months of follow-up.
- The response rate was similar regardless of how many prior therapies patients received.
- The discontinuation rate due to side effects was 1%, which is very low for a CLL therapy.
- The most common side effects were fatigue (20%), diarrhea (17%), and bruising (13%).
- Rates of cardiovascular side effects were low: abnormal heart rhythm (2%), bleeding (2%), and high blood pressure (1%).
Based on these results, pirtobrutinib looks to be safe, effective, and well-tolerated in patients who have already been treated with other therapies. There are now two ongoing phase 3 clinical trials of pirtobrutinib recruiting patients. One study is for patients with relapsed/refractory CLL, and it compares a triple combination of pirtobrutinib + venetoclax + rituximab vs. venetoclax + rituximab. The second study is for patients with untreated CLL, comparing pirtobrutinib vs. bendamustine + rituximab. Take a look if you are interested in participating.
Please enjoy this interview with Dr. Mato from the ASH meeting, held in December 2021 in Atlanta, GA, and virtually.
You can read the actual abstracts here: Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study
Take care of yourself first.
Ann Liu, PhD