The Rationale of FLT3 Inhibition in AML
Transcript:Hervé Dombret, MD: With FLT3 inhibition, there are two important things. The first thing is that there are now several inhibitors. I mentioned midostaurin, which was one of the first ones, but there is new development in that field. We now have a short list of several molecules that could inhibit FLT3. What is really important to consider is that all these inhibitors are not targeting exactly the same kinases. All are targeting FLT3—they are FLT3 inhibitors—but some of them are multi-kinase target agents, like midostaurin or sorafenib, for instance. So, it could happen that when using a multi-kinase—targeting agent, you could get some benefit or some beneficial effects by targeting kinases other than FLT3. These are so-called off-target effects, and this is maybe important in the case of sorafenib or midostaurin. When the midostaurin trial results were available, a lot of investigators, including myself, asked the question of, “What could have been the effect of midostaurin in FLT3-negative patients?” It was because of this potential off-target effect of a multi-kinase inhibitor like midostaurin.
The other thing that is important—and in relation with what I mentioned before concerning the secondary event, FLT3 mutation could be a secondary event—is that you cannot expect probably to cure patients by simply inhibiting FLT3. Because if FLT3 is a secondary event, you have to also target the driver event. So, this is a rationale to combine FLT3 inhibition to other treatment. First, to combine it with standard treatment, which was present before, and maybe in the future, combine novel drugs with FLT3 inhibition.
Richard M. Stone, MD: Not all FLT3 inhibitors are the same. There are many drugs that have been developed in the guise of being FLT3-inhibiting, which is based on their ability to inhibit the enzyme in vitro or in cell-free systems. But no enzyme inhibitor is completely specific, because many of our enzymes in our bodies are similar to the other ones and these drugs are not completely specific. So, the FLT3 inhibitors differ on their FLT3 inhibitory spectrum. Do they inhibit FLT3 only, or mainly? Or do they inhibit FLT3 and a lot of other enzymes that may or may not be relevant in the pathophysiology of AML? And there are other issues. Is the drug protein-bound? Is it really bioavailable? Does it have side effects? FLT3 inhibitors are not all the same, and the most important initial difference I would submit is whether or not the inhibitor in question hits both the internal tandem duplication mutation only or whether it hits that one, as well as the tyrosine kinase domain mutation.
Midostaurin, for example, which is one of the putative FLT3 inhibitors tested, is: a) highly protein bound, b) does inhibit both the FLT3 ITD and the tyrosine kinase domain mutation, and c) is fairly promiscuous in other enzymes it inhibits, including c-KIT and even non—tyrosine kinases, like protein kinase C, which is why it was first developed. Actually, midostaurin was used in solid tumors because it was a protein kinase C inhibitor and that was thought to be beneficial in solid tumors. It turns out to not be the case, but when it was found by Griffin, Weisberg, and others to be a FLT3 inhibitor, then it started to be developed in AML.
Transcript Edited for Clarity
