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iwCLL 2025 | Targeting BTKi-resistant CLL using the 4th-generation BTK inhibitor rocbrutinib
Britten Gordon, BS, The Ohio State University, Columbus, OH, discusses the development of rocbrutinib, a 4th-generation BTK inhibitor (BTKi), as a potential therapeutic option for BTKi-resistant chronic lymphocytic leukemia (CLL). He highlights the mechanism of action of this novel BTKi, outlines preclinical findings supporting its potential activity in BTKi-resistant CLL, and comments on where this agent could fit in the future treatment landscape of CLL. This interview took place at the biennial International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2025 in Krakow, Poland.
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Transcript
So we thought that to be able to target both wild-type and mutant BTK could be a pretty viable treatment strategy, as it would be able to overcome some of the common forms of resistance to the current BTK inhibitors. So rocbrutinib is actually able to bind wild-type BTK in a covalent manner similar to Ibrutinib, Acalabrutinib, and Zanubrutinib while also being able to bind into that C481S-mutated BTK in a non-covalent manner like pirtobrutinib or nemtabrutinib...
So we thought that to be able to target both wild-type and mutant BTK could be a pretty viable treatment strategy, as it would be able to overcome some of the common forms of resistance to the current BTK inhibitors. So rocbrutinib is actually able to bind wild-type BTK in a covalent manner similar to Ibrutinib, Acalabrutinib, and Zanubrutinib while also being able to bind into that C481S-mutated BTK in a non-covalent manner like pirtobrutinib or nemtabrutinib. So it’s really got strong efficacy in both those settings, but what we have actually really enjoyed is its efficacy in both that T474I and L528W setting, which really none of the other BTK inhibitors have efficacy across all of those.
So we used a few different models in the BTK inhibitor-resistant setting. We generated TMD8 cell lines that have the point mutations of C481S, T474I, and L528W, and it showed strong efficacy in its anti-proliferative effect and by inhibiting the BCR signaling pathway. Not quite resistant, but it also showed strong efficacy in two separate CLL mouse models and was better than ibrutinib in both of them.
I think in the immediate future, it’s gonna be more of that third or fourth option after patients take, say, the covalent inhibitor, like an ibrutinib, probably progress, take venetoclax, relapse, and go on pirtobrutinib. Eventually, it might come forward due to its activity, but I think the pirtobrutinib versus ibrutinib trial is gonna be telling on if that’s feasible or not.
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