Dr Brown on the Implications of Genomic Data for Pirtobrutinib Use in CLL

Jennifer R. Brown, MD, PhD, director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology, Harvard Medical School, discusses clinical implications from an analysis of baseline genomics and acquired resistance mutations in patients with chronic lymphocytic leukemia (CLL) who progressed on the noncovalent BTK inhibitor pirtobrutinib (Jaypirca).

A systematic evaluation of genomic evolution was conducted in a larger cohort of patients treated with pirtobrutinib in the phase 1/2 BRUIN trial (NCT03740529). Data presented at the 2023 ASH Annual Meeting revealed high response rates with pirtobrutinib in patients with relapsed CLL who expressed frequent baseline BTK mutations. The most common mutations observed at baseline in this population included BTK, TP52, SF3B1, ATM, NOTCH1, PLCG2, and BCL2, which were present in 53%, 49%, 34%, 23%, 20%, 14%, and 9% of patients, respectively. However, these mutations did not predict responses to pirtobrutinib.

At the time of disease progression, acquired resistance mutations were detected in 68% of patients, with multiple mutations observed in 40% of these patients. Notably, 64% of these patients displayed acquired BTK mutations even at baseline, indicating the presence of potential pre-existing resistance mechanisms. Clearance of BTK mutations occurred in 51% of patients.

These findings raise important questions regarding the optimal sequencing of pirtobrutinib and covalent BTK inhibitors in CLL management, Brown begins. Although pirtobrutinib is effective, particularly in patients with relapsed disease, concerns about the development of resistance and its impact on subsequent treatment options remain, she explains. Caution should therefore be used when considering the use of pirtobrutinib before other covalent BTK inhibitors, Brown says. Covalent BTK inhibitors have elicited prolonged responses in certain patients, but the duration of response with pirtobrutinib remains uncertain in comparison, she reports, emphasizing the need for further understanding of how the mutational profiles of pirtobrutinib evolve over time before the routine introduction of the agent in the upfront setting.

Furthermore, the identification of specific mutations associated with resistance to pirtobrutinib opens the possibility of selecting alternative therapies based on the mutational profiles of individual patients, Brown adds. For instance, patients harboring the L528W mutation, which confers resistance to zanubrutinib (Brukinsa), may still respond to acalabrutinib (Calquence). Similarly, ibrutinib (Imbruvica) has shown activity against the T474I mutation and may be a viable treatment option for this patient population, Brown notes. However, the efficacy of these alternative agents in the context of acquired resistance to pirtobrutinib requires further investigation, she concludes.