Dr Wierda on the Genomic Evolution of Pirtobrutinib in Pretreated CLL

William G. Wierda, MD, PhD, professor, medicine, Jane and John Justin Distinguished Chair in Leukemia Research in Honor of Dr. Elihu Estey, section chief, Chronic Lymphocytic Leukemia, center medical director, Department of Leukemia Center, Division of Cancer Medicine, executive medical director, Inpatient Medical Services, The University of Texas MD Anderson Cancer Center, discusses the genomic evolution of pirtobrutinib (Jaypirca) in patients with pretreated chronic lymphocytic leukemia (CLL) based on data from an updated analysis of the phase 1/2 BRUIN study (NCT03740529).

The analysis focused on evaluating resistance mutations, specifically mutations in BTK, both before pirtobrutinib and at the point of progression on pirtobrutinib, Wierda begins. In the BRUIN population of patients who were previously treated with a BTK inhibitor, the objective response rate achieved with pirtobrutinib was 73.3% (95% CI, 67.3%-78.7%), and the median PFS was 19.6 months (95% CI, 16.9-22.1), he shares. However, although the responses were durable, they did not endure over several years.

This analysis shed light on the mechanisms of resistance that emerge in patients progressing on pirtobrutinib after developing resistance to the agent, Wierda explains. In the context of covalent BTK inhibitors, the primary resistance mechanism involves mutations in BTK—especially at C481, he states. This mutation hinders the covalent binding of BTK inhibitors to BTK, rendering them ineffective, Wierda explains. Patients with a BTK C481 mutation who initiated pirtobrutinib often lost this resistance mutation upon progression on pirtobrutinib, he adds.

The analysis also revealed a subgroup of patients progressing on pirtobrutinib who developed alternative resistance mutations in BTK, Wierda says. Despite the disappearance of the BTK C481 mutation, these alternative mutations emerged as key contributors to treatment resistance, he says. Additionally, there was a notable increase in the frequency of mutations in TP53 at the point of progression on pirtobrutinib, Wierda states.

This study holds significance as it sheds light on the dynamic interplay between pirtobrutinib’s influence and the clonal architecture of the patient population, he continues. The observed reduction in the prevalence of BTK C481 mutations and the emergence of alternative mutations in BTK upon pirtobrutinib initiation delineate the intricacies of resistance mechanisms under the pressure of the drug, Wierda concludes.