Dr Alencar on Unmet Needs Associated With BTK Inhibitor Resistance in CLL

“The challenge is that [covalent BTK inhibitors] are extremely effective, but now we're starting to see this resistance and lack of options for these patients [with CLL]. We know that the great majority of patients will do extremely well with these classes [of drugs] and are able to have excellent disease control and very good tolerability for a very long time, but we still see more and more patients that, over time, will develop resistance and won’t have a lot of [treatment options left].”

Alvaro Alencar, MD, a hematologist/oncologist, an associate professor of clinical medicine, and associate chief medical officer in the Division of Hematology at the University of Miami Sylvester Comprehensive Cancer Center, discusses current unmet treatment needs following covalent BTK inhibitor resistance in patients with chronic lymphocytic leukemia (CLL).

Although treatment with BTK inhibitors has shown promising efficacy in patients with CLL, resistance to these drugs leaves patients with a lack of options, Alencar begins. With BTK inhibitors, patients typically have excellent disease control and tolerate the drugs well for a long time, he notes. However, higher incidences of resistance to BTK inhibitors have been seen among patients with CLL.

After resistance to covalent BTK inhibitors and BCL2 inhibitors, treatment with PI3K inhibitors is an option, although these inhibitors are now less frequently used, Alencar says. He also emphasizes that CAR T-cell therapy could be another option after patients develop resistance to BTK inhibitors. Nevertheless, he explains that there’s currently limited access to CAR T-cell therapy in the CLL setting.

An ongoing phase 1 trial (NCT05131022) presented by Alencar at the 2024 ASH Annual Meeting demonstrated the efficacy of an additional potential treatment option beyond BTK inhibitors after patients develop resistance: the novel NX-5948 BTK degrader. An analysis of the data revealed that among patients evaluated for efficacy (n = 30), the overall response rate (ORR) was 75.5% (95% CI, 61.1%-86.7%), and patients with a longer follow-up demonstrated an ORR of 84.2% (95% CI, 68.7%-94.0%).