Bruton’s Tyrosine Kinase in B-Cell Malignancies: Advances in Targeted Therapy - Episode 1

Available BTKi and Their Mechanisms of Action

Mazyar Shadman, MD, MPH, and Jonathon Cohen, MD, MS, introduce available BTK inhibitors used as targeted therapy in B-cell malignancies.

Mazyar Shadman, MD, MPH: Hello, and thank you for joining this Targeted Oncology™ presentation titled “Bruton Tyrosine Kinase in B-cell Malignancies: Advances in Targeted Therapy.”

BTK [Bruton tyrosine kinases] inhibitors play an important role in the treatment of B-cell malignancies. In today’s Precision Medicine in Oncology® program, we’ll discuss the mechanism of action of BTK inhibitors and how they’re used in practice. We’ll review data from clinical trials and talk about patient selection.

I’m Dr Mazyar Shadman. I’m an associate professor of medical oncology at Fred Hutchinson [Cancer Research Center] in University of Washington in Seattle, Washington. Joining me is my colleague Dr Jonathon Cohen, an associate professor of hematology and medical oncology at Winship Cancer Institute of Emory University [in Atlanta, Georgia]. Thank you so much for joining me, Dr Cohen.

Jonathon Cohen, MD, MS: Thank you.

Mazyar Shadman, MD, MPH: Before we start talking about some of the therapeutic approaches and targeted drugs, we know that BTK is a cytoplasmic nonreceptor tyrosine kinase inhibitor that belongs to the TEC kinase family, and it plays a major role in B-cell development. In the B cells, we know that immune responses to antigen are mediated through the BTK interaction and BCR. In some B-cell malignancies we know that the BCR receptor through either antigen-dependent or -independent activities play a central role in the pathogenesis of drugs like CLL [chronic lymphocytic leukemia]. These B-cell BCR signaling aren’t driven by any specific mutation or rearrangement but instead by amplification of pathways like BTK or PI3 kinase. This understanding has led to development of some targeted approaches and medications that have changed our practice and, in some diseases, shifted our approach and our treatment landscape from using mainly chemoimmunotherapy, in the case of CLL, for example, to nonchemotherapy options and targeted drugs.

I wonder if you can give us an introduction on what BTK inhibitors we have available, and then we’ll go ahead and talk about some of the specifics in more details.

Jonathon Cohen, MD, MS: Thank you again for having me. It’s a pleasure to be here. As you mentioned, we know that targeting BTK has been an effective therapeutic approach across a variety of B-cell malignancies. Fortunately we have 3 approved BTK inhibitors, and these all bind covalently with BTK. That will become important as we start talking about some of the newer therapies under development.

The 3 approved therapies are ibrutinib, acalabrutinib, and zanubrutinib. Zanubrutinib is approved for mantle cell lymphoma only, whereas ibrutinib and acalabrutinib are also approved for chronic lymphocytic leukemia, and ibrutinib has additional indications, including marginal zone lymphoma and Waldenström macroglobulinemia. As a result, these are used frequently across a range of B-cell lymphoma subtypes. Although these all target BTK in a similar way, there are some differences among them. Acalabrutinib is given twice daily, whereas ibrutinib and zanubrutinib could both be given daily. In addition, there are some differences in the specificity with which they target BTK and some of the off-target effects, which may impact some of the safety and tolerability of these agents and may have led to the development of some differences in adverse-effect profiles. Fortunately, these are all highly effective therapies that are used frequently in day-to-day practice.

This transcript has been edited for clarity.