The BTK inhibitor nemtabrutinib may offer a new treatment option for patients with relapsed hematologic malignancies such as chronic lymphocytic leukemia and non-Hodgkin lymphoma, according to a recent study published by Woyach et al in Cancer Discovery.
Background
Hematologic malignancies are diagnosed about once every 3 minutes and cause about one death every 9 minutes in the United States. Chronic lymphocytic leukemia and non-Hodgkin lymphoma affect the B lymphocyte, which is responsible for producing antibodies and fighting infections. Chronic lymphocytic leukemia comprises approximately 25% of all leukemia cases, whereas non-Hodgkin lymphoma accounts for 4% of all cancer cases in the United States.
When an antigen enters the bloodstream, it can trigger B lymphocytes to produce antibodies with a set of signals. However, in some individuals, the B cells may begin to divide uncontrollably, leading to the development of cancer instead of fighting infections.
Drugs designed to target B-cell cancer types work by binding to Bruton's tyrosine kinase (BTK), an enzyme involved in the signaling process. The drugs block the action of the enzyme, and as a result, the abnormal B cells may die.
Although most patients initially respond to these drugs, many patients may experience disease progression over time—where the BTK enzyme can mutate to prevent the drugs from blocking its action. Thereafter, the cancer may recur.
“[Hematologic malignancies] that have relapsed after initial treatments can be difficult to treat, and even with our effective [drugs], some patients run out of standard treatment options,” explained lead study author Jennifer Woyach, MD, Co-Leader of the Leukemia Research Program at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James).
Nemtabrutinib was designed to bind to the BTK enzyme even in the presence of common mutations that make other BTK inhibitors ineffective. It is also capable of binding to a number of proteins besides the BTK enzymes that are important in B-cell cancer types.
Study Methods and Results
In a first-in-human trial of nemtabrutinib, researchers assigned 47 patients who received at least two prior therapies for their hematologic malignancies to receive nemtabrutinib once daily. Over 50% of the patients had relapsed chronic lymphocytic leukemia, while the others had non-Hodgkin lymphoma.
They found that nemtabrutinib was effective in about 75% of the patients with chronic lymphocytic leukemia—including those who had mutations in their BTK enzymes—at an optimal dose of 65 mg. The researchers reported that most of the patients experienced disease-free survival for at least 16 months and had no severe side effects.
Conclusions
“The drug is being moved to larger and more definitive trials, where it will be compared against other standard-of-care drugs, and in combination with other active medications,” highlighted Dr. Woyach. “In this trial, nemtabrutinib looks very promising for patients whose cancer has progressed after other treatments,” she concluded.
Disclosure: The research in this study was supported by ArQule. For full disclosures of the study authors, visit aacrjournals.org.
