Pre-Conference Perspectives on Hematologic Malignancies - Episode 6

AML Studies: FLT3 Inhibitors


John Leonard, MD: So, there are a number of drugs now that we’ll move towards that are targeted drugs looking at FLT3 inhibitors and targeting FLT3 mutations of one form or another. I want to look at my notes to get the names right because they’re not on the tip of my tongue, unlike brentuximab. So, gilteritinib. Feel free to correct me if I get it wrong.

Alexander Perl, MD: They roll right off your tongue: Gilteritinib and crenolanib.

John Leonard, MD: So, this was a study looking at, as I understand it, a FLT3 inhibitor primarily in patients with newly-diagnosed AML in combination with chemotherapy.

Alexander Perl, MD: Right, and the background on this is, as we know, a couple of years ago at ASH, one of the plenary abstracts was the ratified study where midostaurin, a very broadly selected kinase inhibitor that happens to inhibit FLT3, was added to standard frontline therapy and improved the survival relative to placebo. So, 7 and 3 plus midostaurin in FLT3-mutated patients improved survival. And now, it’s a standard of care. The real question is, if those nonselected drugs can do that, what about a selective and potentially more potent drug? And so, there are 2 drugs that are being looked at in this setting this year at ASH. This study uses gilteritinib, which is a very selective and highly potent drug that has substantial single agent activity in relapsed/refractory patients added to 7 and 3 therapy, and this is the first time that data with that drug had been presented in a combination regimen. And as you can see, we’re still working out the optimal dosing, but it seems like we can go up to the same doses that were active in single-agent therapy, which seems to be quite tolerable and also the response rates are really quite high. There’s not enough follow-up on this study to really say how well this is working in the long run, but there are median survivals of about a year on this study for the FLT3-mutated patients who were treated. Again, the response rate was more than 90%.

John Leonard, MD: And roughly, again, what percent of AML patients are FLT3-mutated?

Alexander Perl, MD: About one-third are. Maybe one-quarter of them will have a FLT3 ITD, which is really the more sinister of the 2 mutations, and maybe 5% or 10% will have a FLT3 point mutation in the tyrosine kinase domain, which has less of a risk of relapse. But if either of these relapse, the disease is very aggressive and survival short.

John Leonard, MD: OK. And then, the other one we referenced was crenolanib.

Alexander Perl, MD: Yes. Crenolanib is, in many ways, very similar to gilteritinib. These drugs were both developed because they were potent, selective, and also, they went after resistance mutations that have emerged with other FLT3 inhibitors. So, both of those tic those boxes off. They differ a little in pharmacokinetics. Gilteritinib is a long-lived drug. It has a half-life of several days. Crenolanib has a half-life of several hours. So, we don’t know the right answer here. Do you want a short-lived drug so it’s easier to combine with chemotherapy? If you run into toxicity issues that it gets out of the water very quickly? Or do you want a long-lived drug because you can get more continuous inhibition of target? I think we’ll find this out over time.

The data from this study were presented a year ago and what you’re seeing again here is longer follow-up. So, we don’t have a lot more information about response rates. But again, response rates are very high in frontline therapy. The big problem in particular FLT3 ITD-mutated AML is relapse. And what’s encouraging from these data is the relapsed rate was really quite low. There were only 2 relapses amongst 24 patients in remission on this study, which is substantially lower than what one might expect from this population. If we look back historically, FLT3 ITD-positive patients in first CR can have as high as a 70% relapse rate in the first 2 years. Now, the median follow-up here is not that long, but this is very encouraging even for early data. And there is a randomized study looking at crenolanib added to frontline therapy compared to midostaurin added to frontline therapy that’s just about to activate. So, we’ll see whether the data from RATIFY really will be improved by a newer drug.

John Leonard, MD: And do we have any data in these drugs? I know probably single-agent activity is pretty modest, but if you get 1 drug and then you progressed, is there any activity with the other?

Alexander Perl, MD: Yes. So, patients who have progressed with frontline therapy with these agents have been salvaged with the other. If the patients got midostaurin in frontline therapy and then wound up on either crenolanib or gilteritinib, they have responded. That has been true of other FLT3 inhibitors—sorafenib, quizartinib—being salvaged with gilteritinib or crenolanib.

John Leonard, MD: Interesting. Well, it’s good to see progress there. Like in so many other areas, once you have one successful drug with the midostaurin story, then everybody else is going there and then it’s, how can we carve out other areas, make it a little better, etc? But it’s over and over that that seems to happen, which I think is good because ultimately, we’ll have more options and the toxicity profiles no doubt are different, etc.

Transcript Edited for Clarity