Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
A phase 1 clinical trial is recruiting patients to test the safety and tolerability of the new noncovalent BTK inhibitor docirbrutinib.
Who Performed the Research and Where Was it Presented:
Dr. Nitin Jain from The University of Texas MD Anderson Cancer Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Covalent Bruton tyrosine kinase inhibitors (BTKi) are very effective for treating chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) because they block the B-cell receptor (BCR) signaling that CLL cells are so dependent on. However, they must be taken continuously, usually until disease progression or intolerance. Over time, this can lead to the development of resistance mutations that prevent the drug from binding to BTK. This problem has led to the development of noncovalent BTKi, which bind to BTK in a reversible manner and are effective in patients that have developed resistance to covalent BTKi such as ibrutinib, zanubrutinib, and acalabrutinib. Pirtobrutinib was the first noncovalent BTKi to receive FDA approval. This study reported on docirbrutinib, a new noncovalent BTKi in development.
Methods and Participants:
This is an ongoing phase 1b clinical trial in patients with relapsed / refractory B-cell cancers who have received two or more lines of therapy. The study aims to evaluate the safety profile and tolerance of docirbrutinib at different dose levels and identify a recommended dose level.
Results:
- This trial is ongoing, and thus far, 14 patients have enrolled, including nine patients with CLL and those with follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.
- Patients had received a median of four prior therapies, and most patients had progressed on prior covalent BTKi therapy.
- The study is also open to patients who progressed on pirtobrutinib.
- It is still very early in the study, and they are actively recruiting patients.
- Preliminarily, no drug-related atrial fibrillation or bleeding has been observed.
- Some moderate to severe cases of low white blood cell counts (14%) and elevated liver enzymes (7%) have been observed.
- No dose-limiting toxicities have yet been observed at doses up to 500 mg twice daily.
- Five of the nine CLL patients had partial responses, and three had stable disease with a 16-45% reduction in tumor size.
Conclusions:
While pirtobrutinib was the first noncovalent BTKi to receive FDA approval, more noncovalent BTKi are still in development, including docirbrutinib and nemtabrutinib, as well as dual covalent noncovalent BTKi. These drugs could provide more options to patients who have developed resistance to traditional covalent BTKi. Blocking the activity of BTK remains a crucial part of CLL therapy, and it makes sense to find more ways to block it when patients develop resistance mutations to the covalently binding BTK inhibitors (ibrutinib, zanubrutinib, and acalabrutinib).
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Preliminary Results from a Phase 1b Study of Noncovalent Pan-Mutant BTK Inhibitor Docirbrutinib (AS-1763) in Patients with Previously Treated B-Cell Malignancies
If you are interested in participating in this trial, more information can be found here: AS-1763 in Patients With Previously Treated CLL/SLL or Non-Hodgkin Lymphoma.
