Dr. Jeff Sharman and colleagues presented this research at the American Society for Hematology annual meeting held December 2021 (ASH 2021).
Background:
Bruton tyrosine kinase (BTK) inhibitors revolutionized the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Currently available BTK inhibitors, such as ibrutinib and acalabrutinib, work by forming irreversible (covalent) bonds with BTK that inhibit its activity. However, some patients develop resistance mutations such as the C481S mutation at the binding site, which prevents irreversible BTK inhibitors from binding to BTK and render the drug ineffective, resulting in relapse.
To address this, scientists have been studying a new class of drugs known as reversible (non-covalent) BTK inhibitors, which bind differently than irreversible BTK inhibitors. Non-covalent BTK inhibitors such as pirtobrutinib and nemtabrutinib (MK-1026) (ARQ 531) can inhibit both normal (wild-type) BTK and mutated BTK (C481S mutation). Pirtobrutinib has been tested in phase 1/2 clinical trials, and the results showed that it was generally well-tolerated and effective in some hard-to-treat patients. As a next step, researchers are now starting a phase 3 clinical trial that will test the efficacy of pirtobrutinib vs. a comparator group.
Takeaways:
- BRUIN CLL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab.
- Eligible patients are adults diagnosed with CLL / SLL and have been treated with a prior covalent BTK inhibitor. Researchers expect to enroll 250 patients in the study.
- You are not eligible for this study if you have any of the following:
- Central nervous system involvement by CLL / SLL
- Richter transformation
- A significant bleeding event while on a prior covalent BTK inhibitor
- Previous allogeneic stem cell transplant or autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization
- The primary endpoint is progression-free survival.
- Secondary endpoints include overall survival, overall response rate, duration of response, safety and tolerability, and patient-reported outcomes.
Conclusions:
Clinical trials are vital for developing new therapies to treat CLL and SLL. If you are interested in participating in this phase 3 study of pirtobrutinib, more information can be found here.
This is an option worth considering after prior treatment with acalabrutinib. ibrutinib or zanubrutinib
Here is the link to the ASH 2021 abstract for more details.
Take care of yourself first.
Ann Liu, PhD
