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Second-Generation FLT3 Inhibitors in AML: Quizartinib

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, Perelman School of Medicine; Eunice Wang, MD, Roswell Park Cancer Institute
Published: Thursday, Mar 01, 2018



Transcript: 

Harry Erba, MD, PhD: We need to move on to what’s on the horizon. Midostaurin has been approved for FLT3-mutated AML. We’re not quite certain if that’s because it’s directed at FLT3 or if it is a more promiscuous kinase inhibitor, but we’re going to test that now because we have 3 very potent, more selective drugs: quizartinib, gilteritinib, and crenolanib. I’m going to have each of you talk about one. I’m going to have you start with quizartinib, Jorge.

Jorge E. Cortes, MD: Quizartinib was developed as a much more selective FLT3 inhibitor. Eunice mentioned earlier that with this kinome map, you see it light up like a Christmas tree with midostaurin. This is very selective; very few kinases are inhibited. The potency against FLT3 is 10-fold higher than the next kinases that it inhibits. It is much more selective than the others and not as protein bound, which could be beneficial. That led to the initial development of this drug. It went to phase I, and particularly in phase II, it showed very nice activity. Patients with FLT3 mutations showed around 50% of responders. Most of these were CRis (complete remission with incomplete hematologic recoveries). There were a few CRs in that, but most of these were CRis, so there was an incomplete recovery of platelets and/or neutrophils.

One thing that was interesting with the development of quizartinib was that we were way off on our MTD [maximum-tolerated dose] calculations in the initial phase I setting. We started saying that it was 200 mg, and then we learned that grossly exceeded what we can safely do in terms of QTc prolongation, which didn’t translate into clinical problems for the patients. But you don’t want to have too many patients going into the 500-mg range of QTc. So, we learned that lower doses were equally effective in terms of the CR plus CRi rates but greatly diminished the risk of QTc prolongation to the point that now it’s very, very manageable.

It’s shown very good activity, in the 50% range for CR/CRi, which is actually very impressive. Responses are transient. We have single-agent responses. They’re transient but still last a few months. Other than the QTc prolongation, it is a very well tolerated drug. It is given orally, of course. It has now gone to this randomized study in the salvage setting, QuANTUM-R, which is finished, of course. We’re going to see the data soon in randomized salvaged patients with FLT3 mutations who received either quizartinib or the preferred salvage therapy.

It is not an inhibitor that hits D835, so that is one area that’s uncovered. I don’t think that’s very interesting, and it was left out there. But in the non–FLT3-mutated patients, we have about a 30% CR/CRi rate, which is not negligible. That’s something that was left out there because obviously the focus is FLT3-mutated disease, but there is something that in the future, we need to think of what to do with it.

Harry Erba, MD, PhD: The other study that is ongoing is very similar to the RATIFY trial.

Jorge E. Cortes, MD: That’s correct.

Harry Erba, MD, PhD: It is adding quizartinib in sequence with standard 7-and-3 chemotherapy, high-dose Ara-C, and then a 1-year maintenance. In theory, it’s very similar to the QuANTUM-First trial design. That study is ongoing but not accruing so well in the United States anymore.

Alexander E. Perl, MD: Right, because there are alternatives.

Harry Erba, MD, PhD: That’s right. There are alternatives. It’s hard to randomize somebody to a placebo-controlled trial, but it is ongoing, so hopefully we’ll get some answers there.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: We need to move on to what’s on the horizon. Midostaurin has been approved for FLT3-mutated AML. We’re not quite certain if that’s because it’s directed at FLT3 or if it is a more promiscuous kinase inhibitor, but we’re going to test that now because we have 3 very potent, more selective drugs: quizartinib, gilteritinib, and crenolanib. I’m going to have each of you talk about one. I’m going to have you start with quizartinib, Jorge.

Jorge E. Cortes, MD: Quizartinib was developed as a much more selective FLT3 inhibitor. Eunice mentioned earlier that with this kinome map, you see it light up like a Christmas tree with midostaurin. This is very selective; very few kinases are inhibited. The potency against FLT3 is 10-fold higher than the next kinases that it inhibits. It is much more selective than the others and not as protein bound, which could be beneficial. That led to the initial development of this drug. It went to phase I, and particularly in phase II, it showed very nice activity. Patients with FLT3 mutations showed around 50% of responders. Most of these were CRis (complete remission with incomplete hematologic recoveries). There were a few CRs in that, but most of these were CRis, so there was an incomplete recovery of platelets and/or neutrophils.

One thing that was interesting with the development of quizartinib was that we were way off on our MTD [maximum-tolerated dose] calculations in the initial phase I setting. We started saying that it was 200 mg, and then we learned that grossly exceeded what we can safely do in terms of QTc prolongation, which didn’t translate into clinical problems for the patients. But you don’t want to have too many patients going into the 500-mg range of QTc. So, we learned that lower doses were equally effective in terms of the CR plus CRi rates but greatly diminished the risk of QTc prolongation to the point that now it’s very, very manageable.

It’s shown very good activity, in the 50% range for CR/CRi, which is actually very impressive. Responses are transient. We have single-agent responses. They’re transient but still last a few months. Other than the QTc prolongation, it is a very well tolerated drug. It is given orally, of course. It has now gone to this randomized study in the salvage setting, QuANTUM-R, which is finished, of course. We’re going to see the data soon in randomized salvaged patients with FLT3 mutations who received either quizartinib or the preferred salvage therapy.

It is not an inhibitor that hits D835, so that is one area that’s uncovered. I don’t think that’s very interesting, and it was left out there. But in the non–FLT3-mutated patients, we have about a 30% CR/CRi rate, which is not negligible. That’s something that was left out there because obviously the focus is FLT3-mutated disease, but there is something that in the future, we need to think of what to do with it.

Harry Erba, MD, PhD: The other study that is ongoing is very similar to the RATIFY trial.

Jorge E. Cortes, MD: That’s correct.

Harry Erba, MD, PhD: It is adding quizartinib in sequence with standard 7-and-3 chemotherapy, high-dose Ara-C, and then a 1-year maintenance. In theory, it’s very similar to the QuANTUM-First trial design. That study is ongoing but not accruing so well in the United States anymore.

Alexander E. Perl, MD: Right, because there are alternatives.

Harry Erba, MD, PhD: That’s right. There are alternatives. It’s hard to randomize somebody to a placebo-controlled trial, but it is ongoing, so hopefully we’ll get some answers there.

Transcript Edited for Clarity 
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