Differences Between Zanubrutinib and Other BTK Inhibitors for CLL/SLL

Jennifer R. Brown, MD, PhD, from the Dana-Farber Cancer Institute and lead investigator of the ALPINE study (NCT03734016), discusses the mechanism of action of zanubrutinib (Brukinsa)and how it differs from other Bruton’s tyrosine kinase (BTK) inhibitors for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

In the phase 3 ALPINE study, treatment with zanubrutinib was evaluated in patients with relapsed/refractory CLL or SLL.

According to Brown, zanubrutinib is much more specific for BTK than ibrutinib (Imbruvica) in this patient population. However, the zanubrutinib and acalabrutinib (Calquence) are not too different from one another. One of the things that does set zanubrutinib apart from acalabrutinib is its pharmacokinetic (PK) properties and how it remains present in the bloodstream throughout entire dosing intervals.

Transcription:

0:08 | The covalent BTK inhibitors were the first group where ibrutinib was the first-in-class drug. Then zanubrutinib and acalabrutinib are second generation covalent inhibitors. Zanubrutinib is much more specific for BTK than ibrutinib is. Acalabrutinib is also more specific for BTK. That doesn't distinguish them that much, but 1 thing that does distinguish zanubrutinib from both of them is its pharmacokinetic properties. The drug remains present in the bloodstream throughout the entire dosing interval so that if new BTK is generated by the cells, the drug can still inhibit BTK and it's available to inhibit it again.

0:49 | This is not true of ibrutinib and acalabrutinib. After they do their initial inhibition covalently, they don't stay in the bloodstream, so new BTK would not be inhibited until the next dose. That's perhaps the main biological rationale for why zanubrutinib could be more effective than ibrutinib. The other would be that the dosing was optimized to maintain BTK occupancy. Part of that's the PK but part of it's also the dose and schedule.