Noncovalent BTK Inhibitors for Chronic Lymphocytic Leukemia


Susan M. O’Brien, MD, discussed the emergence of noncovalent BTK inhibitors for treating chronic lymphocytic leukemia.

Susan M. O’Brien, MD: A very exciting category of drug are the noncovalent BTK inhibitors. What’s so attractive about being noncovalent? Nothing really. The important point is the reason they’re non-covalent inhibitors is that they bind at a completely different site than all the first-generation inhibitors. What I mean by that is ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa] all bind at the same ATP binding site. We know that a common mechanism of clinical resistance is when mutations occur in that site, with the most common being the Cys481. Right now, if we have that happen, we can’t interchange those BTK inhibitors because the mechanism of resistance is pretty much similar for all of them. If we have the option, we can use venetoclax [Venclexta]–based therapy. It does have an [approval in the relapse setting] as well as a frontline approval, albeit a slightly different regimen approved for relapse with rituximab [Rituxan] to be given for 2 years. What would be nice about this is we now have these inhibitors that work well even in patients with BTK mutations. There are 2 of them in development, there may be more, but there’s 2 that we’ve seen some data from already. One is LOXO-305—that drug now actually has a name which is pirtobrutinib—and then the other drug is MK-1026 [Nemtabrutinib]. Both of those are going to be presented at [the 2021 American Society of Hematology Annual Meeting]. What we know from the original presentations is that their response rates were quite good, but what we don’t know for either of them, and perhaps we’ll get a better handle at ASH on how durable these remissions are. When the original data was presented, the follow-up was very short, less than a year with both drugs. It’s really exciting to be able to have a new group of drugs that would work in the setting of first-generation BTK inhibitor resistance. That would mean that we could also, if we wanted to use one of those drugs once they get approved, continue to have venetoclax as another option if patients then became resistant to those next-generation inhibitors.

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