Dr O’Brien on the Use of Pirtobrutinib in BTK Inhibitor-Resistant MCL and CLL

Susan M. O’Brien, MD, associate director, clinical science, Chao Family Comprehensive Cancer Center, medical director, Sue and Ralph Stern Center for Clinical Trials and Research, University of California, Irvine (UCI), professor, Division of Hematology/Oncology, Medicine, UCI School of Medicine, discusses the use of pirtobrutinib (Jaypirca) for patients with hematologic malignancies who developed resistance to BTK inhibition.

Mutations associated with resistance to BTK inhibitors commonly occur at the agent's binding site, O’Brien begins. These include acquired mutations at residue C481, which is the kinase domain for covalent BTK inhibitors such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), she explains.

The noncovalent BTK inhibitor pirtobrutinib was specifically developed to combat BTK inhibitor resistance. The agent was designed to bind to tumor cells independent of this residue, O’Brien explains. Preclinical data from in vitro studies have shown that pirtobrutinib is highly effective in both wild-type and C481-mutated cells and could be a potential alternative for patients resistant to covalent BTK inhibition, O’Brien adds.

In the phase 1/2 BRUIN trial (NCT03740529), pirtobrutinib was evaluated in patients with MCL, as well as a subset of patients with CLL/small lymphocytic lymphoma (SLL), O’Brien continues. Within this subset, a substantial number of patients had refractory disease, and had previously been treated with venetoclax (Venclexta). O’Brien also notes that median number of prior lines was 3 in the overall population.

Pirtobrutinib produced an overall response rate (ORR) of 82% in the total population (n =247), and an ORR of 79% in heavily pretreated patients who had progressed on both venetoclax and a prior BTK inhibitor, O’Brien details. Median progression-free survival (PFS) was 19.6 months in the total population, and 16.8 months in the heavily pretreated group, she states. Response rates were consistent regardless of mutational status, age, or previous therapies.