Vecabrutinib for Chronic Lymphocytic Leukemia (CLL)
by Dr. C.H. Weaver M.D. 4/2020
Currently available Bruton tyrosine kinase (BTK) inhibitors, such as Imbruvica (ibrutinib) and Calquence acalabrutinib have become a mainstay of chronic lymphocytic leukemia (CLL) treatment. Inhibiting the BTK enzyme has produced some very effective treatments however these treatments bind irreversibly, and some patients ultimately develop resistance mutations which prevent these irreversible BTK inhibitors from binding to BTK and render the drug ineffective resulting in relapse.
Several novel precision cancer medicines are being tested in clinical trials that belong to a new class of drugs known as reversible or “non-covalent” BTK inhibitors. These medications bind in a different way than irreversible BTK inhibitors. Even though they all target BTK, they are all slightly different from each other and have slightly different properties. They include LOXO-305, ARQ-531, and vecabrutinib (SNS-062).
About Vecabrutinib (SNS-062)
Vecabrutinib is a selective, reversible, non-covalent BTK inhibitor (BTKi) with potent in vitro inhibitory activity against both wild type and C481S-mutated BTK, the most common mutation detected in patients with CLL relapsing on treatment with covalent or irreversible BTK inhibitors.
The results of a small early clinical trial evaluating vecabrutinib in 27 patients were published at the December 2019 American Society of Hematology meetings. The trial included 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 researchers have reported that vercabrutinib was safe and well tolerated at the evaluated doses to date. In fact vecabrutinib may be better tolerated than irreversible BTK inhibitors. In the trial four patients with CLL, three of whom had BTK C481S mutations had their disease stabilized and these patients remained on treatment 72 to over 196 days at the time of publication. One patient with CLL BTK C481S showed improvement in B-symptoms and decreased tumor burden. Vecabrutinib appears to be well tolerated and has clear evidence of clinical activity in CLL, even in patients with the C481S mutation. Evaluation of higher treatment doses in ongoing.