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Resistance to BTKi Therapy


Callie Coombs, MD, reviews how patients develop resistance to Bruton Tyrosine Kinase inhibitor (BTKi) therapy and how BTKi resistance is managed.

Ryan Haumschild, PharmD, MS, MBA:Dr Coombs, how do patients develop resistance to BTKi [Bruton tyrosine kinase inhabotor] therapy? How is that resistance managed?

Callie Coombs, MD: Resistance is a problem that’s real in the setting of any targeted therapy. In the BTKi setting, the most common mechanism of resistance is through the acquisition of mutations at the C4D1 residue of the BTK protein that prevents the covalent binding of ibrutinib, acalabrutinib, and zanubrutinib. They all work similarly. There can be downstream mutations in PLC𝛾-2, but those are a little less common. For simplicity, we’ll say C4D1 is the most common mechanism. If a patient has intolerance to ibrutinib, acalabrutinib or zanubrutinib, it can still work. If they have progression on any of those, the drugs will not work because they all share the same mechanism of resistance. A key thing is that pirtobrutinib has a distinct binding mechanism that’s agnostic to the presence or absence of the C4D1 S mutation because it’s an irreversible or noncovalent BTK inhibitor. That’s another reason that it’s so exciting: it has activity to prolong the BTK pathway, as we’ve talked about.

Ryan Haumschild, PharmD, MS, MBA: Having agents with additional benefits that can exceed some of that resistance is great. To accentuate your points, Dr [Brian] Koffman, about having patients on that BTKi pathway longer and pursuing that within their treatment. The future looks exciting for us, especially around some of these resistance patterns.

Transcript edited for clarity.

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