We’ve been discussing Bruton tyrosine kinase inhibitors in our recent conference coverage. To recap, the Bruton tyrosine kinase (BTK) signaling pathway is really important because chronic lymphocytic leukemia (CLL) has an “addiction” to it, so inhibiting the BTK enzyme has produced some very effective treatments.
Most currently available BTK inhibitors, such as ibrutinib and acalabrutinib, are irreversible (covalent). However, some patients develop resistance mutations which prevent irreversible BTK inhibitors from binding to BTK and render the drug ineffective resulting in relapse.
Scientists are trying to develop new types of BTK inhibitors to expand the treatment options available to patients who relapse. Several drugs being tested in clinical trials belong to a new class of drugs known as reversible (non-covalent) BTK inhibitors which bind in a different way than irreversible BTK inhibitors. These include LOXO-305 which we previously discussed here, ARQ-531, and vecabrutinib (SNS-062). Even though they all target BTK, they are all slightly different from each other and have slightly different properties.
At the annual meeting of the American Society of Hematology (ASH) 2019, our own Dr. Brian Koffman interviewed Dr. John Allan, a CLL specialist at Weill Cornell in New York City. They discussed preliminary results from a clinical trial of a new reversible BTK inhibitor, vecabrutinib (SNS-062).
In the lab, vecabrutinib can inhibit both normal BTK and mutated BTK (C481S mutation). This clinical trial is the first time it has been tested in patients.
This is a phase 1/2 trial of vecabrutinib in 27 patients with advanced B-cell malignancies who had received 2 or more prior treatment regimens and whose cancer continued to progress while on therapy with an irreversible BTK inhibitor. The main goal of a phase 1/2 clinical trial is to determine if the drug is safe, and then to determine the best dose of a new treatment.
- Patients in this study had cancers that were likely to mutate (76% had a TP53 mutation, 48% had a BTK C481 mutation, 20% had a PLCg2 mutation).
- Thus far, vecabrutinib appears to be very safe, and most side effects have been mild.
- Though it is early on, researchers have not seen any evidence that vecabrutinib causes heart damage, which can sometimes be caused by drugs used to kill cancer cells.
- Researchers are trying to find the best dose which gives the most efficacy with low toxicity.
- Once they determine the best dose, they can expand the study to more patients.
Though clinical trials are still in their early stages, so far it appears that reversible BTK inhibitors such as vecabrutinib are safe and much better tolerated than irreversible BTK inhibitors.
We hope that as these clinical trials continue and expand we will continue to see positive outcomes for patients. These studies provide good reason for patients, especially those with resistance mutations, to be hopeful.
Please enjoy this interview with Dr. Allan from December 2019 at ASH in Orlando, FL.
You can read the actual ASH abstract here: Ongoing Results of a Phase 1B/2 Dose-Escalation and Cohort-Expansion Study of the Selective, Noncovalent, Reversible Bruton’S Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Cell Malignancies
Take care of yourself first.
Ann Liu, PhD