I think these are likely strongly reflective of drug-specific toxicities. We’ve known now for over a decade that the different tyrosine kinase inhibitors contribute to muscle mass loss, and it’s likely just how they work as tyrosine kinase inhibitors. I think the question that this study raises of seeing a difference in lenvatinib plus everolimus compared to cabozantinib is the difference from differences in the tyrosine kinases targeted by lenvatinib versus cabozantinib, or is it the addition of everolimus, which is an mTOR inhibitor, which has known impacts on metabolic phenotype and insulin signaling...
I think these are likely strongly reflective of drug-specific toxicities. We’ve known now for over a decade that the different tyrosine kinase inhibitors contribute to muscle mass loss, and it’s likely just how they work as tyrosine kinase inhibitors. I think the question that this study raises of seeing a difference in lenvatinib plus everolimus compared to cabozantinib is the difference from differences in the tyrosine kinases targeted by lenvatinib versus cabozantinib, or is it the addition of everolimus, which is an mTOR inhibitor, which has known impacts on metabolic phenotype and insulin signaling. So that could be contributing as well to the finding with lenvatinib plus everolimus. And then for the second question of whether this is reversible, objectively, we don’t know. I think many of us suspect that if you stop the tyrosine kinase inhibitor and go over to belzutifan that we see an improvement in weight gain and likely changes in body composition, although we intend to study that in the future. If you go from a tyrosine kinase inhibitor to another tyrosine kinase inhibitor, I doubt you’re going to see a reversal of that to the losses that occurred.
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