ESH CLL 2022 | Pirtobrutinib resistance in CLL: early findings

Yeah. So, pirtobrutinib, again, is a non-covalent BTK inhibitor. It is active in patients who have developed the known mechanisms of resistance to the covalent inhibitors, for example, the cys 481 mutations. We are just beginning to know the earliest data on resistance to pirtobrutinib, particularly in heavily pre-treated patients who’ve previously been exposed to covalent BTK inhibitors, and many of whom have multiple other mutations, including cys 481 mutations.

Our group, under the leadership of the Abdel-Wahab Laboratory at MSKCC, recently published a paper in the New England Journal of Medicine. We’ve identified several mutations in BTK at the site where we suspect LOXO-305 or pirtobrutinib would bind, that would render that molecule ineffective, either binding ineffective, or have changed the kinase itself from one that’s catalytically active to one that’s catalytically dead. The big mystery, I think, at this point in time is what resistance to non-covalent BTK inhibitors will look like in terms of earlier lines of therapy. And there there’s still a large… The evidence is still quite missing and we don’t have any evidence because we haven’t really treated patients in the frontline setting or a large patient population who’ve previously never seen a covalent BTK inhibitor. So just very, very early data, but quite compelling in a heavily pretreated population, again, where we’re seeing mutations in BTK, which are different and distinct from the ones that were previously noted for patients who received a covalent inhibitor.