Dr Alencar on the Rationale of Investigating BTK Degraders in CLL

“The idea of the study [is] to develop a drug that will degrade [or] completely eliminate this receptor and therefore prohibit the scaffolding mechanism…even when [BTK] inhibitors, be it covalent and noncovalent, no longer work.”

Alvaro Alencar, MD, hematologist/oncologist, associate professor, clinical medicine; associate chief medical officer, University of Miami Sylvester Comprehensive Cancer Center, explains the rationale of the ongoing phase 1 trial (NCT05131022) evaluating the novel BTK degrader NX-5948 in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Findings from the study were presented at the 2024 ASH Annual Meeting.

Alencar notes that BTK degraders play a crucial role in targeting a part of the B-cell receptor pathway that goes beyond BTK inhibitors. He explains that although BTK inhibitors also target the B-cell receptor pathway, they also completely block the receptor. Of these BTK inhibitors, there are 2 classes, Alencar says, including covalent and noncovalent BTK inhibitors. However, when these drugs are used, patients develop resistance in the receptor, he says. Alencar notes that when the receptor is completely inhibited, downstream activation is still there because the dead receptor acts as scaffolding. Alternative receptor pathways come through the dead receptor and can still activate the cell downstream, he explains.

The analysis presented at the ASH Annual Meeting evaluated efficacy in 30 patients, who experienced an overall response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%); among patients with a longer follow-up, responses deepened to an ORR of 84.2% (95% CI, 68.7%-94.0%). Regarding safety, the most common treatment-emergent adverse effects included purpura/contusion (36.7%), fatigue (26.7%), petechiae (26.7%), and neutropenia (23.3%). Grade 3 or greater neutropenia occurred in 18.3% of patients with CLL.

Alencar emphasizes that the rationale of the phase 1 study is to develop a drug that will degrade and eliminate the B-cell receptor pathway. This prohibits the scaffolding aspect of the dead receptor and maintains activity when either covalent or noncovalent BTK inhibitors no longer work, he concludes.