Dr Fisher on Mechanisms of Resistance with Covalent BTK Inhibitors in CLL

David C. Fisher, MD, assistant professor, medicine, Harvard Medical School; institute physician, Dana-Farber Cancer Institute, discusses mechanisms of resistance observed in patients with chronic lymphocytic leukemia (CLL) who were previously treated with covalent BTK inhibitors as part of the phase 1/2 BRUIN study (NCT03740529).

An analysis of this study revealed a high prevalence of acquired non–BTK mutations among patients treated with pirotubrutinib (Jayprica) who had prior covalent BTK inhibitor exposure.

Pirtobrutinib is a non-covalent BTK inhibitor that effectively inhibits both wild-type and C481S-mutated BTK, thereby overcoming resistance that can arise with covalent BTK inhibitors due to the C481S mutations, Fisher begins. The study found that disease progression is driven by the emergence of various mutations, including TP53, NOTCH1, PLCG2, and BCL2 mutations, he details. Some of these mutations may be present in small amounts at the start of therapy and expand over time, but are undetected by standard mutational analysis, leading to resistance, Fisher explains.

In patients who progressed on pirtobrutinib, 44% harbored BTK mutations, 24% had non–BTK mutations, and 32% had no detectable mutations, suggesting the involvement of unidentified resistance mechanisms, he reports. Overall, 68% of patients had acquired mutations, with the most frequent being gatekeeper mutations at T474X and kinase-impaired mutations at L528W he adds.

These findings highlight the complexity of resistance to non-covalent BTK inhibitors and suggest the need for ongoing research to identify and overcome these resistance mechanisms, Fisher says. The study emphasizes the evolving nature of resistance in patients treated with pirtobrutinib and the importance of continued efforts to understand and address the mutations that drive resistance, particularly in those with prior covalent BTK inhibitor exposure, Fisher concludes.