ASH 2025 | Genomic assessment of acquired mutations in patients with CLL treated with nemtabrutinib

I’m very excited about this analysis. We’ve been studying CLL for some time because the disease allows access to the tumor cells directly through a blood sample. And so we’ve been able to look at the cells before, during, and after treatment. And what we’ve observed is that even following patients without therapy, there’s subclonal evolution, where subclones that have mutations that are acquired may gain an advantage over their neighboring subclones, and there may be expansions and contractions of various subclones, even without therapy. Now, when you apply therapy, you actually put a bottleneck on that, and the survival of the subclones that can resist therapy are the ones that win out, and they can actually grow in the proportionate number. And so I think it’s very important for us to use this as a model to understand not just CLL therapy, but therapy for cancer in general. So what we’ve actually been able to advocate doing, and Merck has been very willing to help participate in this, is to look at patients treated in the BELLWAVE study. This study is looking at a novel non-covalent BTK inhibitor called nemtabrutinib. This inhibitor is not, it’s agnostic to the C481 mutation that actually mitigates the effectiveness of covalent inhibitors such as ibrutinib, acalabrutinib, or zanubrutinib, and somewhat akin to pirtobrutinib in that it does not require a covalent bond to the BTK in order to achieve inhibition. However, it has a different spectrum of activity in preclinical data, simulated by Dr. Stilgenbauer in Germany. Actually, it’s found that some of the mutations that confer resistance to even pirtobrutinib may actually not confer resistance to nemtabrutinib. So this actually represents an excellent opportunity for us to analyze patients who are treated on this study. Some of these patients have had multiple rounds of therapy. They may have become resistant to BTK inhibitors, and they have acquired mutations that we can then trace in real time by looking at samples before therapy and at various time points during therapy. So we’re able to achieve this, and we have next generation sequencing in 100 patients with clinical simulated data on 71 patients. I’m going to report on this at this ASH meeting, and what we can see is that subclones that confer some of these mutations that have resistance actually are being downregulated during therapy, and that’s quite encouraging, including some high-risk mutations that we worry about that also contribute to disease progression. We have seen some telltale signs of a few clones that might be coming up, and this may portend potential mechanisms of resistance in BTK or perhaps PLC gamma or downstream of the BCL receptor signaling complex. And I think this is very exciting because what we can actually surmise from this is testing in real time what types of subclones might be sensitive to therapy and which ones might gain an advantage and become resistant to therapy. I wish this could be applied to all targeted therapies and that companies would take an active search in looking at this because in CLL we have an excellent model system in which to be able to apply these technologies and gain information in real time about potential future mechanisms of drug resistance that can really help patients in terms of finding other drugs or in defining combinations that might mitigate that resistance.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.