New mutations may have implications for BTK inhibitor use in chronic lymphocytic leukemia
Justin Taylor, MD, spoke with Healio about a study he and colleagues conducted to examine mechanisms of resistance to noncovalent Bruton tyrosine kinase inhibitors.
Taylor — assistant professor at Sylvester Comprehensive Cancer Center at University of Miami School of Medicine — and colleagues performed genomic analyses of specimens obtained from patients with chronic lymphocytic leukemia who had undergone treatment with pirtobrutinib (LOXO-305; Eli Lilly, Loxo Oncology), a noncovalent Bruton tyrosine kinase (BTK) inhibitor. Investigators obtained the samples at the time of disease progression.
“We discovered new BTK mutations occurring in patients who developed resistance to pirtobrutinib,” Taylor told Healio. “They were not the usual BTK mutations that are seen as resistance to the first-generation of BTK inhibitors. These were new mutations that had not been studied before.”
Researchers then engineered these mutations into cancer cell lines. Results showed these mutations conferred resistance to pirtobrutinib and other noncovalent BTK inhibitors.
Investigators also tested earlier-generation BTK inhibitors, and some of the mutations also conferred resistance to those agents, as well.
“We don’t want the message to be that [pirtobrutinib] is not effective, because it is,” Taylor told Healio. “However, [clinicians] should be aware of these new mutations and — given the fact some of them cause resistance to other types of BTK inhibitors — it is something we need to keep an eye out for. This may have clinical implications for the way BTK inhibitors are given in the future.”
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