Noncovalent BTK Inhibitors May Fill Unmet Medical Need in CLL

Skye Montoya

In the chronic lymphocytic leukemia (CLL) treatment landscape, covalent Bruton's tyrosine kinase inhibitors (BTKi) have made headway, leading to a paradigm shift in both the front-line and relapsed and/or refractory settings. However, patients often discontinue treatment with these inhibitors due to toxicity or disease progression.

As a result, noncovalent BTKis, which bind reversibly to the BTK target, have been studied to potentially address the limitations seen with covalent BTKi. Clinical trials are evaluating these agents, and the FDA has already granted 1, pirtobrutinib (Jaypirca), approval for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL).

In the phase 1/2 BRUIN study (NCT03740529), pirtobrutinib was evaluated for use in patients with CLL, and researchers found that resistance arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. With phase 3 trials underway, pirtobrutinib appears promising for patients with CLL requiring treatment after a covalent BTKi.

“By looking at these resistance mutations that caused resistance to not only covalent BTK inhibitors, but also noncovalent BTK inhibitors, we can start focusing our research on new approaches to therapies to combat mutations that cause resistance across all inhibitors,” Skye Montoya told Targeted Oncology^TM, in an interview.

blood cells : © Dr_Microbe - stock.adobe.com

In the interview, Montoya, a PhD candidate at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, discussed her research on noncovalent BTKi and mechanisms of resistance in CLL.

Targeted Oncology: Can you discuss your research on noncovalent BTK inhibitors in CLL?

Montoya: The New England Journal of Medicine paper was discussing resistance that arose from patients that were being treated in the clinical trials with pirtobrutinib, which is the most recent noncovalent BTK inhibitor. These noncovalent BTK inhibitors arose to overcome some of the resistance that was seen to covalent BTK inhibitors. Specifically, the resistance that occurs at the C481S mutation. The use and treatment with noncovalent BTK inhibitors is wonderful for patients as far as a second-line treatment to overcome resistance that might have been seen for covalent BTK inhibitors. But our research focused on why it stopped working for certain patients or how patients acquired mutations that could cause resistance.

From that study, we were able to use samples pre-treatment and at the time of resistance or disease progression, and identified different mutations in the catalytic domain of BTK. Then, we used several approaches to definitively show that these mutations were causing the resistance to the drug. The novel and surprising thing was that some of these mutations were actually kinase-dead, which is where a lot of the excitement, for me at least, came from, because it asks a very curious question of, why would mutations that prevent inhibition of BTK through BTK inhibitors also the kinase dead? So then it sparked into 2 different projects: defining the mechanism of how these kinase dead BTK mutations work, and then also coming up with new ways to treat patients that have these BTK mutations. That is a lot of what our newest paper is going to be focused on.

What were some of the findings from that study?

The [findings] show the safety and tolerability of this drug. The drug was well-tolerated in patients with CLL, and it was recently approved as a frontline treatment for MCL, patients with mantle cell lymphoma. The ability to treat relapsed patients with CLL with this noncovalent BTK inhibitor and overcome the resistance seen from ibrutinib treatment or other covalent BTK inhibitors was very exciting for patients.

From a research standpoint, how do you think these findings will influence CLL research moving forward?

In the treatment of CLL, we have targeted therapies for BTK that work wonderfully. But with a chronic disease like CLL, these treatments are meant to be for lifetime use. We are seeing it more commonly in patients after long-term treatment that mutations can arise and resistance can occur. By looking at these resistance mutations that caused resistance to not only covalent BTK inhibitors, but also noncovalent BTK inhibitors, we can start focusing our research on new approaches to therapies to combat mutations that cause resistance across all inhibitors.

For example, the BTK degraders that are being used now, like NX-2127, are able to overcome a lot of the resistance mutations that we've seen and it's a new approach. It is different from BTK inhibitors because it doesn't have to bind for as long or as strongly and it's able to overcome the resistance seen from the mutations.

The work that we're doing to define these mutational resistance mechanisms and showing that these mutations cause resistance across the board of treatment options, has pushed the field in a new direction as far as developing novel therapies or new approaches to treatments

What unmet needs still exist in the space?

When it comes to the treatment of CLL, a definitive, frontline, or even sequential treatment, is still something that we need to understand better. Do you give patients frontline treatment with noncovalent inhibitors or covalent inhibitors? Is it better to save noncovalent inhibitors in case resistance occurs to covalent inhibitors, or vice versa? And, of course, there's also approaches when it comes to combination therapies, degraders, and other targets with CLL.

Understanding how these mutations arise and what causes the mutations in the first place are what we need to focus on. Are they from the treatment? Were they there originally? Were they just selected out from the treatment? Hopefully, by getting a better understanding of that we can definitively address how to treat patients with this for the long-term.

REFERENCE

Montoya S, Thompson MC. Non-covalent bruton's tyrosine kinase inhibitors in the treatment of chronic lymphocytic leukemia. Cancers (Basel). 2023;15(14):3648. Published 2023 Jul 17. doi:10.3390/cancers15143648