Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Brad S. Kahl, MD: The first-generation BTK inhibitors are considered to be dirty kinases. In other words, they’re not superselective for BTK, and there are a lot of other kinases that get hit as a result of this nonselectivity. Generally what that means is more off-target effects. If you’re a patient taking a BTK inhibitor, there is potentially more toxicity. So the more selective your BTK inhibitor, presumably the better the safety and the adverse-effect profile will be for that particular agent. So that’s really the goal with second- and third-generation BTK inhibitors: To develop more BTK selectivity, have fewer off-target effects, and as a result, less toxicity.
We consider ibrutinib to be a first-generation BTK inhibitor. It was really the first one on the market, and it’s had a huge impact in some of these diseases that we manage. Second-generation BTK inhibitors would be considered things like acalabrutinib, which is now FDA-approved for use in relapsed mantle cell lymphoma. And there are newer BTK inhibitors being developed by a variety of different companies. Probably the BTK inhibitor that’s furthest along after ibrutinib and after acalabrutinib is one called zanubrutinib. Zanubrutinib is an even more selective BTK inhibitor, hopefully with fewer off-target effects than earlier versions of BTK inhibition.
Steven P. Treon, MD, PhD: We’re privy now to new BTK inhibitors that are being looked at in the treatment of Waldenström macroglobulinemia. These include both acalabrutinib as well as zanubrutinib. And this year, actually at both at ASCO [American Society of Clinical Oncology Annual Meeting] and the EHA [European Hematology Association] meeting, and more recently at the International Waldenström’s Macroglobulinemia Workshop, we began to learn about the activity of these drugs in Waldenström disease. And so far most of the data out there are early stage data, but what we see is that these inhibitors actually demonstrate high levels of activity in Waldenström compared with what we see with ibrutinib. And the adverse-event profiling is very, very similar. There are some subtle differences that we see—perhaps more headaches, at least in the initial introduction of acalabrutinib, which can be treated with caffeine. But all in all, these are very comparable. The difference with ibrutinib is that these are administered twice a day versus once a day, and perhaps convenience issues will be more important to consider.
When one also looks at the activity of these drugs, it’s important to keep in mind that there a number of off-target kinases that may be very important to the growth and survival of Waldenström. And with ibrutinib, we know that HCK itself is targeted. This is an SRC family member that is very important to the activation of BTK as well as the AKT and ERK pathways. So as one looks at the kinase profiling of these drugs, one will see that it’s not just about BTK. There are other targets, including HCK, which can be impacted, and this may help us discriminate some of these kinases.
Brad S. Kahl, MD: The major toxicities that we see with BTK inhibitors, as I mentioned, are rash and diarrhea. There’s a risk for hypertension, which can be significant and hard to manage. There’s a risk for atrial fibrillation and bleeding, which we believe is a result of effects on platelets, as well as myalgias and arthralgias. And some people need to stop their BTK therapy because of adverse effects, because of toxicities. So clearly, if we could develop BTK inhibitors that have even better safety profiles—I mean, they have good safety profiles. They’re generally well-tolerated medicines, but for some patients there definitely are problematic toxicities. And to develop BTK inhibitors that could minimize that would be a good development for patients.