Medically reviewed by Dr. Brian Koffman
The Bottom Line:
The majority of CLL patients who had previously relapsed on covalent BTK inhibitors responded well to pirtobrutinib therapy. When disease progression occurred, most patients had acquired one or more mutations, including new BTK mutations.
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Brown from Dana Farber Cancer Institute and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2023.
Background:
Bruton tyrosine kinase inhibitors (BTKi) are very effective for treating chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). Still, one of the major challenges with their use is the development of resistance mutations over time. Most of the BTKi currently in use (ibrutinib, acalabrutinib, zanubrutinib) are covalent BTKi, meaning that they bind irreversibly to a specific site on BTK and inactivate it. However, over time, CLL cells can develop mutations at that binding site (most commonly the C481S site), so covalent BTKi cannot bind effectively. Pirtobrutinib is a non-covalent BTKi that binds reversibly to different sites on BTK, so patients who have the C481S mutation can still benefit from pirtobrutinib therapy. However, CLL is smart, and patients can still develop resistance to pirtobrutinib. For this study, researchers wanted to learn more about how resistance to pirtobrutinib develops.
Methods and Participants:
This study included patients from the BRUIN study (a phase 1/2 trial of pirtobrutinib for B cell malignancies) who met the following criteria:
- Had CLL that was previously treated with a covalent BTKi
- Their disease progressed on pirtobrutinib therapy
- Had next-generation sequencing data available from baseline and from disease progression on pirtobrutinib
Results:
- For this analysis, 86 patients were included, and 86% had discontinued their previous BTKi due to disease progression.
- Patients had previously been treated with ibrutinib (90%), acalabrutinib (17%), and zanubrutinib (2%).
- The majority of patients (83%) responded to pirtobrutinib.
- At baseline, 53% of patients had a BTK mutation, and the most common BTK mutation was C481S, which is the mutation that prevents covalent BTKi from binding.
- Among the 42 patients with C481S mutation, over half (55%) completely cleared this BTK variant while on pirtobrutinib.
- At the time of disease progression, 69% of patients had acquired one or more mutations.
- Most patients (56%) acquired a non-BTK mutation, and 44% acquired a BTK mutation (most commonly T474I or L528W).
Conclusions:
The majority of CLL patients who had previously relapsed on covalent BTK inhibitors responded well to pirtobrutinib therapy, which is in line with the results from the complete BRUIN study. When disease progression occurred, most patients had acquired one or more mutations, including new BTK mutations. There is a suggestion from other studies that some of these new mutations might also render the CLL cells resistant to some of the covalently binding BTKi, but that remains to be proven. What is intriguing is that over half of those on pirtobrutinib cleared the original C481 resistance mutation, suggesting, at least in theory, that those patients might be able to benefit from being rechallenged with a covalent BTKi. This strategy is already being tried in some patients. How we best sequence these therapies in the future will depend on what ongoing research teaches us, but it’s good to have all these options.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Genomic Evolution and Resistance during Pirtobrutinib Therapy in Covalent BTK-Inhibitor (cBTKi) Pre-Treated Chronic Lymphocytic Leukemia Patients: Updated Analysis from the BRUIN Study
Take care of yourself first.
Ann Liu, PhD
