Transcript:Harry Erba, MD, PhD: This is a very interesting discussion, but let’s turn to the third FLT3 inhibitor that we have. We’re not going to have time today to talk about crenolanib, but I do want to mention that it’s in clinical development as well. Mark, tell us about quizartinib.

Mark J. Levis, MD, PhD: Quizartinib has been a long time in coming. Midostaurin and this other drug, lestaurtinib, first came out at these pan-targeted things that happened to hit FLT3. And so, as a designer drug, a company set about to make a drug specifically to target FLT3, and that was ultimately quizartinib. What we learned about that drug in the relapsed setting is that it cleared the blast rapidly. It did so through differentiation. The responses were typically these things called CRis [complete response with incomplete hematologic recoveries]. OK, what the heck is a CRi?

Well, the drug has got some activity against the receptor c-kit. It’s in the same family as FLT3, and so you do get some myelosuppression with that, some anemia, and some thrombocytopenia. And so, they never quite get the full CR [complete response]. And with that information a large trial was launched. “OK, we’re going to do it right. We’re going to do a randomized trial. We’re going to compare it to the treatment that you have just said doesn’t work very well in those patients, with a dismally bad survival result. Take a relapsed FLT3-ITD [internal tandem duplication] AML [acute myeloid leukemia] patient and give them either MEK or FLAG-IDA [fludarabine/ara-C/G-CSF/idarubicin] chemotherapy. And back into the hospital. And guess what? It’s not likely to work. And we are going to randomize that.”

And the trial that we’re talking about is QuANTUM-R, which randomized patients to that versus single-agent quizartinib. So this was a doctor’s choice randomization. They could choose low-DAC [decitabine], FLAG-IDA, or MEK. Do what you will. And the endpoint was overall survival. This was a very rigorous trial, and it accrued obviously over several years. It was a 2-to-1 randomization of over 300 patients.

Alexander Perl, MD: And you had to pick the randomization choice prior.

Mark J. Levis, MD, PhD: You had to choose your treatment beforehand, choosing intensive or not, and once that was done the patients were randomized. And it met its primary endpoint. You look at the curves and, yes. Is it dramatic? Does it cure everybody? Absolutely not. The responses are primarily CRis. So the population was a dreadful population, of course. They were newly relapsed, within 6-months remission duration, and that’s a disaster. Or, they were primary refractory.

Alexander Perl, MD: And after, a transplant.

Mark J. Levis, MD, PhD: Not surprisingly, the response rate in the control arm, chemotherapy, was dismally low. And, of course, the survival curve was poor. Quizartinib monotherapy clearly was better. Again, was it dramatically better? I would say certainly enough that you can see it from across the room. But importantly the patient is at home watching TV, coming in to the clinic maybe twice a week instead of spending yet another month in the hospital getting a completely ineffective regimen.

Alexander Perl, MD: Or a patient who couldn’t get to transplant could get a transplant, and I think that is a question we need to look at a little more carefully to say, are the transplants given to the patient to respond to either of these salvage therapies clinically meaningful? Because the numbers overall were small, but if you needed to get to transplant, which we think of as the best therapy for relapse to AML, you could do so much more easily. There were many more patients transplanted in the quizartinib arm.

Naval G. Daver, MD: Yes, I think that’s very important and we do need to follow up, right? Those 32% versus 10%. Because they responded more. More go to transplant. I think that’s going to be the real need eventually. Is there a cure group—2-year, 3-year, or whatever?

I think one of the biostatisticians had shown a couple of years ago this very nice analysis where they took all of the quizartinib phase I, II, III trials, with 500 to 600 patients, and it was very elegantly done. He’s a very well-known statistician. But at the end what he said is, really, when you gave chemotherapy or quizartinib in relapsed AML patients, the only group that had some cure fraction, and it was 15% with transplant, was the quizartinib patient. The chemotherapy was like 1%. So he basically said, “Nothing is good, but with this sort of pill you can get some people to live a long life. With the chemotherapy, you’re just wasting your time.”

Mark J. Levis, MD, PhD: But it’s important to distinguish between the 2 drugs. We just talked about gilteritinib and quizartinib. Quizartinib is a type 2 inhibitor. Yes, it does not have activity against the TKD [tyrosine kinase domain] mutations, but it is poundingly more potent than any other drug out there. It was designed, you know, specifically to nail FLT3 and FLT3 alone. Gilteritinib is a type 1 inhibitor. That’s why it works against the TKDs. It’s a little less potent, and, in fact, I think going forward we’re going to have to find out how we use these drugs in different situations.

Harry Erba, MD, PhD: And you pointed out that the survival difference between quizartinib and the chemotherapy arm wasn’t dramatic. At 1 year, it was 27% versus 20%. The median improved from 20 weeks up to 27 weeks. But there’s an important observation there, and the 2 of you jumped on the fact that the clinician could choose the chemotherapy. That’s artificial, actually. Because what the patient wanted to choose was a FLT3 inhibitor. In fact, 23% of patients who were randomized to get chemotherapy withdrew their consent and….

Mark J. Levis, MD, PhD: Well, they know that stuff doesn’t work too.

Harry Erba, MD, PhD: Well, that’s what I’m guessing. There was gilteritinib. There was crenolanib. There was sorafenib with azacitidine.

Mark J. Levis, MD, PhD: Anything but that chemotherapy stuff.

Harry Erba, MD, PhD: Exactly. And that may have impacted the survival difference that was seen there.

Alexander Perl, MD: But one thing I can throw out there is, if they had access to it after getting their salvage chemotherapy, they’re having access to it then. So for all the people saying, “Oh, I can do this with sorafenib and Vidaza,” no, you can’t. Because under this control arm they had access to that, and you would expect that you would see some evening of those curves.

Naval G. Daver, MD: We had a very hard time enrolling to that study when it was opened for the same reason. You had gilteritinib in parallel, crenolanib in parallel, and quizartinib, and other studies in parallel. So the patient would say, “Well, do you believe in FLT3?”

Mark J. Levis, MD, PhD: Again, a well-designed … you know the study was done. It was a phase III study. Overall survival benefit, the endpoint, was met.

Harry Erba, MD, PhD: Let’s talk a little bit about toxicity. You mentioned gilteritinib. It was like taking a placebo. How about quizartinib? Are there any tolerability issues? There’s this warning about QT [electrocardiogram abnormality], which I know you’re familiar with.

Mark J. Levis, MD, PhD: Oh yes. On a leukemia ward, of all of the bodies everywhere for people who died of QT prolongation, nobody dies of leukemia.

Alexander Perl, MD: But it’s a dose issue. If you give 200 mg of quizartinib, which was the MTD [maximum tolerated dose], you will see a lot of QT prolongation, and some of it’s probably clinically significant, but that’s not what they tested.

Harry Erba, MD, PhD: How did they get up to 200-a-day with quizartinib?

Mark J. Levis, MD, PhD: They designed 3-by-3 design, headed by MD Anderson Cancer Center. And that’s the problem. For a targeted agent, you don’t want a 3-by-3 design. You want to ask, what dose do I need to inhibit the target sufficiently? And, in fact, learning from that was why gilteritinib was designed very differently, where we’re going to choose it based on target inhibition not maximum tolerated dose.

Harry Erba, MD, PhD: And actually, tolerated dose was 300-a-day with gilteritinib, but the FDA approved doses of 120, and going down to 80 based on your data, you still hit the target. And the same was shown with crizotinib, at least with the 30 mg and 60 mg doses.

Mark J. Levis, MD, PhD: Yes, quizartinib actually inhibited the target at the first dose tried—18 mg. That’s how potent it is. And so, we think 60 mg is actually a great dose in this setting. And it frankly has trivial QT prolongation as far as that’s concerned.

Harry Erba, MD, PhD: Other than QT prolongation, are there any suggestions regarding what the toxicities are and how to manage them? Or was it pretty well tolerated?

Mark J. Levis, MD, PhD: Well you’re going to get CRis. And in the relapsed/refractory setting, sure, that’s not a CR Bahamas. You can’t go to the Bahamas. That’s why I think this drug is really better designed for the upfront setting, when we’re used to dealing with those cytopenias and it is really pounding FLT3 from the beginning. And that’s why I’m so excited about the trial that’s going on with this drug now, QuANTUM-First, which is essentially randomized to placebo in newly diagnosed FLT3 patients, duplicating RATIFY with a much more potent FLT3 inhibitor.

Naval G. Daver, MD: I think one important thing is the dynamics of response. Now we have the data with gilteritinib, and the quizartinib data was released. The duration to response is quite different. And I think that may also play a role in selecting a 3.2 month versus 1 month…. And then about this MTD issue. I think we should write a review on this. So there’s not just quizartinib. We’ve got ponatinib. We have Mylotarg. So the other part of research that nobody presented at ASH [the American Society of Hematology meeting], and dasatinib, which is not so sexy, is we’re deescalating therapies across the board. We overshot all the doses and now we’re coming back. So hopefully in the future we do biological effective dosing with antibodies and everything.

Alexander Perl, MD: But you have to be careful with FLT3 inhibitors. Mark has spent a lot of his career saying, “What’s the right dose of this FLT3 inhibitor? Are we really hitting target? Are we hitting it very potently and all the way around the clock, you know, with around the clock inhibition at a potent level?” Because you really need that to get an antileukemic response. And if you go down and you miss the mark, for any reason, you could lose what the drug is there to do. So unless that toxicity is really important, you’ve got to be careful about that.

Harry Erba, MD, PhD: But the other factor is that as we’re thinking about combinations, clearly this is where we’re going because we’re not getting necessarily enough responses, single agents, and that becomes an issue in terms of cytopenias. If you’re going to add something, and most of the agents that we are thinking of adding are going to induce cytopenias, you have to be able to mitigate that. And so, if we’re thinking more about target inhibition rather than let’s max the dose, that will help us get around the issue.

Transcript edited for clarity.