Dr Danilov on Addressing BTK Inhibitor Resistance in Relapsed/Refractory CLL and MCL

Alexey Danilov, MD, PhD, hematologist/oncologist, associate director, Toni Stephenson Lymphoma Center, professor, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, discusses how further research, including the development of NX-2127, may address unmet needs related to disease progression in patients with chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL).

The emergence of BTK inhibitor resistance in CLL or MCL presents a growing challenge, Danilov begins. With the incorporation of BTK inhibitors into the frontline setting for both conditions, innovative strategies are needed to overcome resistance and enhance patient survival outcomes, he explains. Resistance to BTK inhibitors, such as acalabrutinib (Calquence) or zanubrutinib (Brukinsa), is often linked to mutations affecting the BTK binding site, Danilov notes.

Furthermore, the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) has gained approval for patients with CLL and MCL following treatment with other BTK inhibitors, he expands. However, the median progression-free survival generated by pirtobrutinib is less than 2 years in CLL and is even shorter in MCL, Danilov emphasizes. Consequently, the identification of novel strategies to overcome resistance to BTK inhibitors is crucial in lymphoid malignancies, he adds.

The proteolysis-targeting chimeric molecule NX-2127 is being investigated in a multicenter, open-label, phase 1a/1b trial (NCT04830137). This trial will assess the safety and preliminary efficacy of the agent in patients with relapsed/refractory B-cell malignancies. NX-2127 comprises 3 components, Danilov continues. One component acts as a hook that grabs the kinase, the second part serves as a harness, attaching to the E3 ligase, and the third part is a linker, he elucidates. The resulting agent binds to BTK, shuttling it to the proteasome for degradation through its interaction with the E3 ubiquitin ligase. NX-2127 also alters the function and substrate activity of the E3 ligase that regulates the activation of immune cells, much like lenalidomide (Revlimid), Danilov says. Accordingly, NX-2127 operates as a BTK degrader with additional immunomodulatory functions, he concludes.