CLL and Waldenström’s macroglobulinemia are good examples of tumors in which BTK function is nearly essential for those cancers to thrive. If the therapeutic target is essential to the tumor, increased selectivity will almost always benefit the patient because you can hit that target while minimizing the effects on normal tissues and other processes.  

BTK inhibitors target multiple mechanisms, including B-cell growth, cell adhesion, trafficking, and homing, and all of these mechanisms are important to the survival of malignant B cells in CLL. This may explain why BTK inhibitor monotherapies work well in CLL, whereas remissions with BTK inhibitor monotherapy are not as persistent in mantle cell lymphoma. BTK inhibition likely only acts against a subset of the key mechanisms in mantle cell lymphoma. Further, mutations that interfere with one of these mechanisms of action may result in a less robust response. This has been shown in Waldenström’s macroglobulinemia, where patients with mutations affecting the SDF-1/CXCR4 adhesion mechanism do not do as well on ibrutinib. 

So, for malignancies where hitting a single target disrupts multiple physiologic mechanisms that are important to the tumor, such as BTK inhibition in CLL, drug selectivity is important. Acting at multiple sites other than the intended target may cause more toxicities and side effects. There has been some interesting work in a mouse model showing that ibrutinib inhibits the C-terminal Src kinase, and this is likely a mechanism through which ibrutinib leads to atrial fibrillation (ie, ibrutinib-treated mice had inducible atrial fibrillation, an effect that was reproduced in mice lacking BTK but not in acalabrutinib-treated mice). 

Conversely, if a kinase inhibitor is less selective and thereby disrupts other mechanisms that are important to the cancer cell, this could be favorable. For example, nemtabrutinib (formerly known as ARQ 531 and MK-1026) is a reversible BTK inhibitor that also has activity at many other sites, so it has the potential to be a multikinase inhibitor. This kind of activity from a BTK inhibitor might be advantageous if it interferes with other mechanisms that are important in, for example, Richter’s transformation. Thus, in diseases where multiple differing pathways are important, less selectivity can sometimes be an advantage when a more precisely targeted drug will not provide disease control. 

Importantly, selectivity is just one of the many factors that are considered when establishing the role of an emerging compound in the CLL treatment paradigm. Pirtobrutinib is an investigational, third-generation, highly selective, reversible BTK inhibitor, and there is discussion in the field about conducting clinical trials to move it forward to the front line. The mechanism of resistance to reversible kinase inhibitors may involve gatekeeper mutations, and we may lose the ability to switch to alternative BTK inhibitors in patients who develop these mutations during treatment with reversible BTK inhibitors. Further, the sequencing of BTK inhibitors from reversible to irreversible, or from irreversible to reversible, will need to be examined in future studies—not just 1 study, but many. We should be cautious when treating our patients with reversible BTK inhibitors until we are certain that we are not compromising the long-term benefits of the irreversible inhibitors.