Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and Memorial Sloan Kettering Cancer Center have shown that a small group of patients experienced treatment-resistant mutations in a clinical trial for the targeted therapy pirtobrutinib. The paper was published in the New England Journal of Medicine (NEJM).
“We want to understand the mechanisms that govern cancer resistance against pirtobrutinib, which has tremendous potential against chronic lymphocytic leukemia (CLL) and other blood cancers,” said Sylvester researcher Justin Taylor, M.D., assistant professor of medicine in the Division of Hematology, and co-senior author on the paper. “Fortunately, resistance was rare — we only found it in nine patients out of hundreds.”
Pirtobrutinib is part of a new generation of targeted therapies that respond more flexibly to cancer mutations. The drug inhibits enzymes called Bruton’s tyrosine kinase (BTK), which can play a major role in cancer cells’ uncontrolled growth.
Targeting a Specific Mutation
This new inhibitor targets BTK enzymes containing a specific mutation, which helps them escape the therapeutic effects of older BTK inhibitors. This flexibility could make pirtobrutinib an excellent follow-up treatment for patients who have relapsed disease and could even make it a first-line treatment.
“There’s one mutation, called C481S, that leads to resistance,” said co-author Alvaro Alencar, M.D., Sylvester investigator and associate professor of clinical medicine. “When CLL patients develop this mutation, previous generations of BTK inhibitors do not work, but pirtobrutinib does, which gives us this great option to treat patients who have developed resistance. But then we have to ask the question: Will it work forever?”
The NEJM study found that, for a small group of patients, pirtobrutinib does face resistance. While this is not the best news for people with resistant cancers, it does offer direction for researchers and clinicians hunting new therapeutic options. By identifying likely mutations beforehand, this work gives patients and their oncologists new insights to prepare a response if the treatment stops working.
“We have this new treatment that could help a lot of patients, but we can’t forget the people it doesn’t work for,” said Skye Montoya, a Ph.D. candidate in the University of Miami’s Cancer Biology Program and co-author on the study. “It’s exciting to be fighting for that smaller group and trying to find answers for them.”
Great Potential for Patients
While resistance to pirtobrutinib generates genuine concerns, the drug has so far performed well in clinical trials and has only produced relatively minor side effects. A 2021 paper, published in The Lancet, showed pirtobrutinib has great potential to help patients who have become resistant to previous BTK inhibitors. Drs. Taylor and Alencar were co-authors on that study, as well.
Pirtobrutinib is now entering a phase 2 trial and will be combined with other drugs, such as venetoclax, which encourages cancer cell death. The authors are cautiously optimistic these combinations could further mitigate resistance.
“Because pirtobrutinib has relatively few side effects, we can do combination studies with other drugs,” Dr. Taylor said. “Venetoclax has already been approved for CLL and has a completely different mechanism of action than pirtobrutinib, which we hope will circumvent resistance.”