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, 

 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 

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 

The BRUIN study identified a spectrum of mutations in patients who progressed on pirtobrutinib. Acquired 

 mutations were detected in 44% of these patients. However, 24% of patients had non-

 mutations, and in 32% of cases, no identifiable mutations were observed, indicating the presence of alternative mechanisms of resistance.

 mutations associated with pirtobrutinib resistance were observed, including mutations in 

. These mutations likely contribute to disease persistence by activating pathways that bypass BTK inhibition or by promoting cellular survival independent of the BTK pathway.

 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 

 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 

-mutated malignancies who progress on pirtobrutinib.

Videos

David C. Fisher, MD, discusses pirtobrutinib resistance mechanisms that may develop during therapy in patients with CLL 

Dr Fisher on the Integration of Bispecific Antibodies and CAR T-cell Therapy into CRS Treatment 

David C. Fisher, MD, institute physician, Medical Oncology, Dana-Farber Cancer Institute; assistant professor of medicine, Harvard Medical School, discusses the integration of treatment with both CAR T-cell therapy and bispecific antibodies into the therapeutic landscape for patients with cytokine release syndrome (CRS).

CAR T-cell therapy can be associated with unique challenges, particularly in the management of CRS, Fisher begins, noting that it requires specialized care, including the rarer use of IL-6 inhibitors such as tocilizumab (Actemra). He emphasizes that many centers may not have extensive experience in managing these adverse effects, which can make the transition to adopting CAR T-cell therapy more complex. Having required personnel with experience in managing these protocols is essential for successful integration into clinical practice, he explains.

Fisher also highlights the role of bispecific antibody therapies like glofitamab-gxbm (Columvi) and epcoritamab (Epkinly), which may offer a more accessible treatment option for centers not fully prepared to handle the intensive monitoring required by CAR T-cell therapy. 

Glofitamab is approved for a limited treatment duration of 9 months

epcoritamab, which is approved for indefinite use

, are both effective alternatives. However, in practice, indefinite therapy can be challenging to implement, and Fisher suggests that many clinicians may opt for limited treatment duration with both agents.

A key strategy for simplifying the integration of these therapies is step-up dosing, Fisher continues. Step-up dosing, particularly with bispecific antibodies like epcoritamab, can help mitigate the risk of severe CRS and allow for outpatient administration. Fisher explains that optimizing this approach may significantly reduce the need for inpatient care, easing the burden on healthcare systems while maintaining safety for patients.

As CAR T-cell therapy becomes more established, Fisher concludes that clinicians should focus on gaining expertise in CRS management, selecting appropriate therapies, and exploring strategies like outpatient dosing to make these treatments more accessible. Ongoing advancements in the field, including the development of new agents and combinations, will continue to shape the future of CAR T-cell therapy in oncology practice.

David C. Fisher, MD, discusses treatment with bispecific antibodies and CAR T-cell therapy, respectively, for patients with cytokine release syndrome.

Dr Fisher on Potential 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 

-mutated BTK, thereby overcoming resistance that can arise with covalent BTK inhibitors due to the 

 mutations, Fisher begins. The study found that disease progression is driven by the emergence of various mutations, including 

 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 

 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 

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.

David C. Fisher, MD, discusses resistance mechanisms observed among patients with CLL who were previously treated with covalent BTK inhibitors.

David C. Fisher, MD

Articles

Dr Fisher on Mechanisms of Resistance to Pirtobrutinib in CLL

Dr Fisher on the Integration of Bispecific Antibodies and CAR T-cell Therapy into CRS Treatment

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