There are several noncovalent (reversible) BTK inhibitors that are currently in development, including pirtobrutinib (formerly LOXO-305) and nemtabrutinib (formerly ARQ 531 and MK-1026). I have been involved in studies investigating both agents, and we have seen some encouraging data thus far. 

At the recent 63rd American Society of Hematology Annual Meeting and Exposition, data were reported from early phase trials in patients with previously treated CLL. In the study with pirtobrutinib in relapsed or refractory CLL, the overall response rate was approximately 68%, which is very encouraging. Responses seemed good regardless of whether patients discontinued BTK inhibitor therapy due to progression or toxicity. Many of these individuals had also received a previous BCL-2 inhibitor. This was very impressive, as it means that we may have another line of therapy on the horizon for patients with CLL in whom BTK inhibitors or BCL-2 inhibitors are no longer working. 

Further, we also shared data from a phase 2 dose expansion study with nemtabrutinib in 9 cohorts of patients with different B-cell non-Hodgkin lymphomas. Like pirtobrutinib, nemtabrutinib had promising antitumor activity in patients with CLL who were exposed to multiple lines of therapy. Noncovalent BTK inhibitors were designed to overcome a form of resistance that may occur with the covalently bound BTK inhibitors (ie, ibrutinib, acalabrutinib, and zanubrutinib). An example of these mutations includes the C481S BTK mutation. With nemtabrutinib, there is speculation that apparent efficacy in the setting of PLCγ2 mutations may be due to the inhibition of other kinases, but it is still early days.

There is still a lot to be learned about how reversible BTK inhibitors work in B-cell malignancies. In addition to overcoming resistance mutations, there may be other reasons why they work that I think still need to be investigated. Pirtobrutinib appears to work quite well in patients with mantle cell lymphoma (MCL) who were previously treated with BTK inhibitors; the C481S mutation may be less of an issue in MCL than in CLL. 

It is not completely clear why these drugs work as well as they do in patients with MCL. One reason may be related to the reversible bonding mode; they do not appear to be impacted by the intrinsic rate of BTK turnover. Another reason may have to do with their pharmacologic properties. Because noncovalent BTK inhibitors are reversible, relatively high serum levels are needed to maintain binding to receptor sites. 

In summary, these agents are very promising, but studies that have larger patient enrollments are needed to verify the safety and efficacy of noncovalent BTK inhibitors in patients with CLL.