Zanubrutinib has a cleaner kinome than ibrutinib in that it hits fewer off-target kinases, said Ian Flinn, MD, PhD, director of lymphoma research at Sarah Cannon Research Institute.
Zanubrutinib has a cleaner kinome than ibrutinib; it hits fewer off-target kinases, and we’ve seen less reoccurrence of adverse events that led to ibrutinib treatment discontinuation, said Ian Flinn, MD, PhD, director of lymphoma research at Sarah Cannon Research Institute and director of the Sarah Cannon Center for Blood Cancer at Tennessee Oncology in Nashville.
How is zanubrutinib performing among patients previously intolerant to other BTK inhibitors?
Zanubrutinib, of course, is a next-generation BTK [Bruton tyrosine kinase] inhibitor. We know from preclinical studies that it has a cleaner kinome, that it doesn't hit as many off-target kinases as ibrutinib does. As a consequence, we think this will translate into a better safety profile.
This was born out in a randomized phase 2 trial in Waldenström macroglobulinemia, in which patients were randomized to receive ibrutinib or zanubrutinib. And in that study, we found that there was much less of the adverse events, such as atrial fibrillation, seen with zanubrutinib than with ibrutinib, and this held true for many of the other adverse events associated with ibrutinib.
And so with that background, we thought that trying this drug in patients who could no longer take ibrutinib, that maybe we could keep people on therapy with zanubrutinib that could not be on ibrutinib. And that was really the case here. We saw that 88% of the 32 patients who were treated did not have reoccurrence of the adverse event that led to discontinuation of ibrutinib, and in 8 patients in whom it did reoccur, it occurred at a lower level. So 7 out of 8 patients had a much lower level of the adverse events, and efficacy was maintained in these patients. So from an efficacy standpoint, I don't think anybody ever had any questions about zanubrutinib. In this case, it shows that it's a better-tolerated drug than ibrutinib.
What is the importance of keeping patients on BTK inhibitors for longer periods?
I think it's key to keep people on BTK inhibitors for longer periods because unlike venetoclax, which gets patients like CLL [chronic lymphocytic leukemia] patients into a deep, undetectable MRD [minimal residual disease] level, BTK inhibitors, while highly efficacious, we've known since their inception that they do not get to drive these very deep remissions. So if you take someone off a BTK inhibitor, regardless of the disease, then you would expect progression in a relatively short period of time. And so, hopefully, progression-free survival leads to improvement in overall survival and thus keeping people on a BTK inhibitor is key with this when given as a single agent compared to perhaps other therapies that include venetoclax.