Margaret von Mehren, MD: Regarding the secondary mutations, there is lots of discussion about how and why these occur. Clearly, when we look at the tumor cells, we find they all exist within 1 individual cell, although they may differ between different cells. Many have suggested that this is something that was always present—that they were always there—and just with the selection pressure of effective therapy they now become more present and more prominent in a tumor mass because they’re not being controlled by therapy.
In terms of thinking about why I would change therapy, most of the tyrosine kinase inhibitors that we use have a very similar mechanism of action. They’re really trying to inhibit the ATP activation of the kinase. Imatinib, Sutent [sunitinib], and regorafenib do that, as does avapritinib.
One drug that is different and unique in terms of mechanism of action is ripretinib. It essentially works by binding the KIT and PDGFR-α molecule and blocking it in a state where it cannot become activated. These kinases tend to switch from an active to an inactive conformation of the protein, and they do that in part by a loop that flips into the activation site. Ripretinib essentially binds the molecule in 2 spots, preventing that loop from being able to get into the activation site. So that is a different mechanism of action and may be helpful when we’re thinking about resistance, because, at this point, we believe that ripretinib is somewhat agnostic—it doesn’t care what the mutation is. I think with time we’re going to learn more and more about how the drug works clinically, and we will better understand whether that’s a completely true statement or not. Certainly, it is likely that, like other drugs, the tumor cells are going to figure out a resistance mechanism, which we will be learning about as we continue to use that drug.
Transcript edited for clarity.
Case: A 68-Year-Old Man With Gastrointestinal Stromal Tumor