Dr Choi on the Potential Role For BTK Degraders in Relapsed/Refractory CLL

Michael Choi, MD, hematologist/medical oncologist, associate professor of medicine, Moores Cancer Center, University of California San Diego (UCSD) Health, discusses key mechanistic differences between BTK degraders and BTK inhibitors in the management of relapsed/refractory chronic lymphocytic leukemia (CLL), as well as highlights how this approach could address unmet needs within the CLL treatment paradigm.

Clinicians have become increasingly familiar with the use of BTK inhibitors in recent years, Choi begins. However, the emergence of degraders represents a novel and notable advancement in targeting the B-cell receptor signaling pathway, he states. BTK degraders aim to go beyond the inhibition of BTK by leveraging the ubiquitin proteasome pathway to completely degrade the kinase receptor, Choi details. Through this mechanism, BTK degraders may be able to overcome point mutations affecting inhibitor binding with a high degree of specificity, making them an appealing drug class for further investigation, he explains.

Several BTK degraders are currently in development, Choi continues. The observed toxicity profile of this drug class aligns with that of BTK inhibitors, and remissions have been documented, he adds. Promising early results were seen with the novel BTK degrader BGB-16673, which was well tolerated and produced clinically meaningful on-target effects in patients with relapsed/refractory B-cell malignancies, according to results from the phase 1 BGB-16673-101 study (NCT05006716) presented during the 2023 ASH Annual Meeting.

Ongoing exploration of BGB-16673 is being conducted at USCD, Choi states, adding that some patients have achieved partial responses with the agent despite being refractory to previous treatments. This development is not only a positive outcome for patients but also generates interest in the innovative nature of this approach, he says. Unlike continued efforts to improve upon existing variations of BTK inhibitors, BTK degraders represent an entirely new approach in terms of chemistry and pharmacology, Choi emphasizes. This not only bodes well for the ongoing success of these therapies, but also opens up the possibility for targeting other pathways and devising novel treatment strategies for patients in the future, he adds. Overall, the advent of degraders marks a significant step forward in the field, offering a potential new avenue for addressing the challenges of refractory diseases, Choi concludes.