Mark J. Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland, discusses a phase 1, first-in-human study of irreversible FLT3 inhibitor FF-10101-01 in relapsed or refractory acute myeloid leukemia (AML), the data of which were presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Transcript

I am Mark Levis. I am a professor of oncology and the director of the Adult Leukemia Program here at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

Recently, we have had approval of gilteritinib, which is a highly effective FLT3 inhibitor that we spent several years developing, and are very pleased with it, it is my favorite drug around here. I direct the leukemia program, and we have got lots of patients that are on gilteritinib.

However, as a tyrosine kinase inhibitor targeted against FLT3, much like BCR-ABL inhibitors, we want more than one. If we had stopped at imatinib 20 years ago, patients definitely would have not been as well off as they are now.

While gilteritinib is a great drug, there are some things that can be improved, for example, resistance to gilteritinib while primarily conferred by activations of the RAS pathway. You can also get resistance to gilteritinib with the emergence of the "gatekeeper mutation," so-called F691L, and there are non-canonical mutations in FLT3 that probably also confer resistance to gilteritinib. A drug that would hit those would be useful.

In addition, gilteritinib is fairly profoundly impacted by FLT3 ligand, the cytokine that is produced in response to a lot of different things leukemia patients are going through. A drug that was less affected by ligand would be useful.

Finally, the pharmacokinetics of gilteritinib, we thought they were ideal because they last a long time in the patient, the drug has a very long half-life. That causes some drug interaction problems and even runs us into myelosuppression.

We would like to stop the drug, but guess what? The drug is in the patient for the next 3 weeks. You can not stop it quickly. All told, there are certainly things we can improve upon to come up with a drug that complements gilteritinib, does not replace it.

FF-10101 was developed by some of my colleagues in Japan, and it is an irreversible FLT3 inhibitor, much like ibrutinib. It has very different pharmacokinetic and pharmacodynamic properties compared to gilteritinib.

It is impervious to the effects of FLT3 ligand because it binds irreversibly to the receptor. It pretty much inhibits all of the point mutations and non-canonical things that you can find in FLT3, we think, or the large majority of them.

It overcomes that very minor weakness of gilteritinib. Also, it has a short half-life and is irreversible. It bombs in quickly, shuts off FLT3, and then leaves the body. We can dose it accordingly so we have a little more control.

Again, it makes a nice complement to gilteritinib. That is what led to, "Gee, let’s make another FLT3 inhibitor since the first one worked so well."

This was a reasonably conventional study for a FLT3 inhibitor. It was a Phase 1 dose-escalation where we were interested, of course, in safety and tolerability, but primarily identifying a dose that consistently inhibited FLT3 in vivo in patients taking it. We used what we call a plasma inhibitory activity assay to identify the correct dose.

One of the immediate surprising things was we said, "Well, OK. We have an irreversible drug. Give it once and walk away." It turns out the FLT3 mutant receptor has a very rapid turnover. The cells quickly make more.

If your drug is there and turns off the receptor and then the drug leaves, the cell will, 3 hours later, make a whole new set of mutant receptors that are not inhibited. It turns out you have got to have continuous coverage of this drug for 24 hours a day. Therefore, we adjusted our dosing schedule to BID dosing, which worked fine, and we scaled up accordingly.

The other thing that we encountered in doing this trial is it is very hard to find a patient with a FLT3 mutation that has not been treated in serial exposures to different FLT3 inhibitors. Almost like being dumped in vats. By the time they get to our study, they have been exposed to 2 or 3 FLT3 inhibitors that are highly resistant to that mechanism of therapy.

That said, we still did see responses in some FLT3 mutant patients that had been heavily exposed to FLT3 inhibitors. That was encouraging. When we got up to levels that were safe, tolerable, and inhibited FLT3 continuously in these patients, we did see the expected levels of responses.

We had a clean CR in an untreated patient with a FLT3 mutation, and several CRIs in patients that had been exposed to FLT3 inhibitors previously, gilteritinib specifically, and yet still responded to this drug. We think we have identified the dose going forward that we can now expand to a larger study.

We think this drug can stand in the same room as gilteritinib and complements that drug very nicely. This will be the next generation of FLT3 inhibitor. Obviously, we have to get it through a registration process that will involve a large randomized trial, with survival as a benefit, etc. We are still a long ways away.

This, I would say, is a drug that is the next in line. We have identified a dose, it works. Now, the idea is, "OK, how do we get this drug registered?" We run into the difficulty of, "Well, you can not find patients that are not already heavily treated with FLT3 inhibitors. How are we going to carry this forward?"

One option might be a small randomized trial heads up against gilteritinib because, in fact, we think it can stand in the same room as gilteritinib. A relapse patient that has not been treated with gilteritinib could be randomized to get either gilt or this drug. That might be one way of addressing this. Another way would be a registration pathway. We are looking at gilteritinib-resistant patients, and that would be analogous to the drug ponatinib, which was approved for patients that were resistant to the first couple of BCR-ABL inhibitors. This might have a role like that, or if we could go both ways. This is still a ways off, but it is coming. It just depends on how we move it through the registration process.

We know enough about the resistance mechanisms to gilteritinib. We know, for example, this drug is not going to overcome RAS pathway mutations, but it will overcome some of the other weaknesses of gilteritinib or complement them.

Perhaps, this is a drug that might be moved upfront because it probably will combine better with other agents. Because of its shorter half-life and it is more manipulatable, less affected by FLT3 ligand, you could envision upfront use of this drug and maintenance with gilteritinib.

We will probably need to do some sort of head-to-head study. That will probably be the first thing. What we need to do is demonstrate that this drug is safe and tolerable in a population that is going to take it for a long time. We have not done that. These studies are not well designed for that.

We need to ask, "Is this truly as effective as gilteritinib?" and "Is it as safe as gilteritinib in patients that would be taking it for a prolonged period of time?"

Again, this drug is not designed to replace gilteritinib. It is designed to complement gilteritinib. It would be an important addition to our passion, if you will, against this disease.