Dr Omer on Differences Between BTK Degraders and BTK Inhibitors in CLL

“BTK degraders actually degrade the whole protein, while [BTK] inhibitors only inhibit the protein…The protein will not just lose the kinase [with BTK degradation], but also a scaffolding function would be lost with a BTK degrader. With degradation of the whole protein, [BTK degraders] are efficacious against most BTK mutations that develop from BTK inhibition.”

Zulfa Omer, MD, an assistant professor of Clinical in the Department of Internal Medicine at the University of Cincinnati College of Medicine, discussed how BTK degraders operate, the fundamental differences that separate this class from BTK inhibitors, and what future research needs to address to better understand how to utilize them optimally for chronic lymphocytic leukemia (CLL) management.

Omer began by outlining the key difference between BTK degraders and inhibitors, pointing out the importance of each name. BTK inhibitors simply inhibit the BTK protein, whereas BTK degraders initiate degradation. With BTK degradation, the scaffolding of the kinase is eliminated on top of degrading the protein, she added. These differences are key to the appeal of BTK degraders, since BTK mutations that often develop with BTK inhibitors are less of a challenge for efficacy when the whole protein is degraded, Omer explained.

Sequencing within the CLL treatment paradigm remains the biggest questions with BTK degraders, she underscored. Questions remain on whether BTK degraders should be utilized the frontline setting, or if they should be reserved in later lines of therapy upon relapse during or after BTK inhibitor–based therapy, according to Omer. She highlighted how moving forward, the CLL field should focus on gathering data that demonstrate differences in responses depending on when in the treatment course BTK degraders are given to patients. Ultimately, Omer concluded by underscoring the importance of understanding mechanisms of resistance for BTK degraders in helping clarify optimal sequencing for the treatment.