Dr Fisher on Mechanisms of Resistance to Pirtobrutinib in CLL

David C. Fisher, MD, institute physician, Medical Oncology, Dana-Farber Cancer Institute; assistant professor, medicine, Harvard Medical School, discusses the resistance mechanisms observed during pirtobrutinib (Jaypirca) therapy in patients with chronic lymphocytic leukemia (CLL) previously exposed to a covalent BTK inhibitor, as observed in the phase 1/2 BRUIN study (NCT03740529).

This study evaluated the efficacy and safety of pirtobrutinib, a noncovalent BTK inhibitor, in patients with prior resistance to covalent BTK inhibitors. Fisher notes that one of the most common mutations leading to BTK inhibitor resistance is the C481S mutation. Pirtobrutinib has shown activity against this mutation, demonstrating efficacy where other BTK inhibitors may fail, according to Fisher. However, Fisher highlights that despite this advantage, patients eventually develop resistance to pirtobrutinib as well, driven by a variety of mutations beyond those in BTK itself.

The BRUIN study identified a spectrum of mutations in patients who progressed on pirtobrutinib. Acquired BTK mutations were detected in 44% of these patients. However, 24% of patients had non-BTK mutations, and in 32% of cases, no identifiable mutations were observed, indicating the presence of alternative mechanisms of resistance.

Several non-BTK mutations associated with pirtobrutinib resistance were observed, including mutations in TP53, NOTCH1, PLCG2, and BCL2. These mutations likely contribute to disease persistence by activating pathways that bypass BTK inhibition or by promoting cellular survival independent of the BTK pathway.

Specifically, mutations in TP53 and NOTCH1 are known for conferring aggressive disease phenotypes and treatment resistance in various hematologic malignancies, indicating that pirtobrutinib resistance in these patients may be linked to broader genomic instability.

This complex resistance landscape suggests that although pirtobrutinib provides an effective treatment alternative for patients with C481S and other BTK mutations, durable responses remain challenging. The diversity of resistance mechanisms emphasizes the need for comprehensive genomic profiling to tailor subsequent therapies effectively. For patients who progress on pirtobrutinib, combination therapies or alternative agents targeting non-BTK pathways may be necessary to overcome resistance.

Fisher concludes that the findings from the BRUIN study underscore the importance of understanding both BTK-dependent and -independent resistance mechanisms in optimizing treatment strategies for patients with BTK-mutated malignancies who progress on pirtobrutinib.