Dr Dholaria on the Investigation of Noncovalent BTK Inhibitors in CLL

Bhagirathbhai Dholaria, MBBS, assistant professor, medicine (hematology/oncology), Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, discusses the ongoing examination of noncovalent BTK inhibitors in patients with chronic lymphocytic leukemia (CLL).

Multiple noncovalent BTK inhibitors are under investigation in patients with CLL, including pirtobrutinib (Jaypirca), Dholaria says. This agent was initially approved by the FDA in 2023 for the treatment of patients with relapsed/refractory mantle cell lymphoma. Pirtobrutinib was also evaluated in patients with CLL or small lymphocytic lymphoma (SLL) in the CLL/SLL cohort of the single-arm, multicohort, phase 1/2 BRUIN trial (NCT03740529), in which the agent yielded an overall response rate (ORR) of 72% (95% CI, 63%-80%), all of which were partial responses. Furthermore, the median time to response with pirtobrutinib in this cohort was 3.7 months (range, 1.7-27.9), and the median duration of response was 12.2 months (95% CI, 9.3-14.7). Notably, in patients with CLL/SLL who had received a prior BTK inhibitor, the ORR was 73.3% (95% CI, 67.3%-78.7%). The BRUIN trial findings supported the 2023 FDA approval of pirtobrutinib for adult patients with CLL/SLL who have received 2 or more prior lines of therapy, including a BCL-2 inhibitor and a BTK inhibitor.

Another noncovalent BTK inhibitor on the horizon for patients with CLL is nemtabrutinib (ARQ-53), Dholaria explains. Initial findings from the single-arm, phase 1/2 MK-1026-001/BELLWAVE-001 trial (NCT03162536) showed that whennemtabrutinib was given at a daily dose of 65 mg, it elicited an ORR of 75% in patients with CLL/SLL that was relapsed or refractory to at least 2 prior therapies. Updated data from this trial showed that at a median follow-up of 4.8 months (range, 0.1-38.8), the ORR in the CLL/SLL cohort was 56% (95% CI, 42%-69%).

Other noncovalent BTK inhibitors are in the pipeline as well and long-term clinical data from larger patient subsets may be available in the future, Dholaria concludes.