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Quizartinib in AML

Panelists: Elias Jabbour, MD, MD Anderson Cancer Center; Martin S. Tallman, MD, Memorial Sloan Kettering Cancer Center; Richard M. Stone, MD, Dana-Farber Cancer Institute; Harry Erba, MD, PhD, University of Alabama; Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center
Published: Thursday, Feb 02, 2017


Transcript:

Elias Jabbour, MD:
Harry, I want you to talk to us about quizartinib. We had sorafenib for a while, and then we have midostaurin, hoping it gets an approval soon. But, I want to know from you about your studies using quizartinib. Is it better? More potent? What are the state-of-the-art drugs today?

Harry P. Erba, MD, PhD: So, quizartinib, also previously known as AC220, is another orally bioavailable FLT3 inhibitor. What distinguishes it from midostaurin is it’s a little bit more selective than midostaurin and sorafenib for FLT3 mutations, although it still does have some other targets such as c-Kit, which may be important in some of the toxicities. The thing that distinguishes it from other next-generation FLT3 inhibitors such as crenolanib and gilteritinib, ASP2215, is that it does not inhibit an FLT3 enzyme with a tyrosine kinase domain mutation, which may be an important feature since patients who were treated in the phase I and expansion studies of quizartinib, when they develop resistance often, some of these patients had tyrosine kinase domain mutations. But, it makes sense to, based on the preclinical and the phase I data showing activity of quizartinib with about 50% response rates, bring it forward into initial therapy. And so, the QuANTUM-First trial is an international trial that is very similar in design to the RATIFY trial, CALGB 10603.

It’s a study for patients up to the age of 75. There are going to be 536 patients that are treated on the study, about 250 centers. And patients will be randomly assigned 1:1 to receive standard induction chemotherapy, high-dose cytarabine, and then nothing or observation, or the same thing with quizartinib for 14 days during induction, post high-dose Ara-C, and then as a maintenance. So, it’s very similar. The primary endpoint of the study is going to be event-free survival.

A nuance of the study that I think is important, especially for this group of patients who tend to present a very proliferative disease—the ones that are truly driven by FLT3—is that patients can undergo screening for the FLT3-ITD mutations centrally. And if they have it, they get put on the study. But, they can start the daunorubicin or idarubicin initially, and then get randomized and put on drug at day 8. So, that study has just started. We’ve enrolled our first patient in it, but it has a long way to go. And speaking then, finally, to this question of which anthracycline and which dose, the study allows the treating physician to use daunorubicin at 60 mg or idarubicin at 12 mg.

Elias Jabbour, MD: So, moving forward in the future, you have all these drugs available. How do you sequence them, which one do you choose: quizartinib, sorafenib, or midostaurin?

Harry P. Erba, MD, PhD: Well, let me just say the field is changing very quickly. I think most of us at this table, in a way, expect that midostaurin will get a label in the very near future, at least in the United States. And quite frankly, the QuANTUM-First study will need to be done as an international study because it may be very difficult to randomize patients in the near future in the United States to an arm that does not have a FLT3 inhibitor in it. So, the playing field is going to change when midostaurin comes along and these other drugs will need to be compared. Because, finally, we don’t know why there was a benefit with midostaurin. We assume it’s because it was inhibiting FLT3 mutations, but it also targets other tyrosine kinases, which may be actually very important in the benefit that we saw.

Elias Jabbour, MD: So, Richard, today we have all these tests done. For physicians in the community, should we wait to get all these tests back before we decide on therapy? Let’s say you have somebody with AML. You check for the karyotype, and rule out APL rapidly. But, in order to design, what is the best for the long term? You need to wait to get the FLT3 mutation level, or start chemotherapy and later on catch up and add…

Richard M. Stone, MD: We’re talking about a patient who I think is going to get 3+7 based induction chemotherapy right now. So, in that scenario, at the moment, you don’t have to wait to treat the patient, even when midostaurin becomes available, as Harry just said, since the drug isn’t due to start based on the RATIFY trial until day 8. The only problem with that is you might make the patient ineligible for other clinical trials, should they be available, with other agents. Nonetheless, as a community doctor, you can certainly start the patient and wait for the results, or you should get them back within a week. Obviously, you’ll need to know by that point of time.

Transcript Edited for Clarity
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Transcript:

Elias Jabbour, MD:
Harry, I want you to talk to us about quizartinib. We had sorafenib for a while, and then we have midostaurin, hoping it gets an approval soon. But, I want to know from you about your studies using quizartinib. Is it better? More potent? What are the state-of-the-art drugs today?

Harry P. Erba, MD, PhD: So, quizartinib, also previously known as AC220, is another orally bioavailable FLT3 inhibitor. What distinguishes it from midostaurin is it’s a little bit more selective than midostaurin and sorafenib for FLT3 mutations, although it still does have some other targets such as c-Kit, which may be important in some of the toxicities. The thing that distinguishes it from other next-generation FLT3 inhibitors such as crenolanib and gilteritinib, ASP2215, is that it does not inhibit an FLT3 enzyme with a tyrosine kinase domain mutation, which may be an important feature since patients who were treated in the phase I and expansion studies of quizartinib, when they develop resistance often, some of these patients had tyrosine kinase domain mutations. But, it makes sense to, based on the preclinical and the phase I data showing activity of quizartinib with about 50% response rates, bring it forward into initial therapy. And so, the QuANTUM-First trial is an international trial that is very similar in design to the RATIFY trial, CALGB 10603.

It’s a study for patients up to the age of 75. There are going to be 536 patients that are treated on the study, about 250 centers. And patients will be randomly assigned 1:1 to receive standard induction chemotherapy, high-dose cytarabine, and then nothing or observation, or the same thing with quizartinib for 14 days during induction, post high-dose Ara-C, and then as a maintenance. So, it’s very similar. The primary endpoint of the study is going to be event-free survival.

A nuance of the study that I think is important, especially for this group of patients who tend to present a very proliferative disease—the ones that are truly driven by FLT3—is that patients can undergo screening for the FLT3-ITD mutations centrally. And if they have it, they get put on the study. But, they can start the daunorubicin or idarubicin initially, and then get randomized and put on drug at day 8. So, that study has just started. We’ve enrolled our first patient in it, but it has a long way to go. And speaking then, finally, to this question of which anthracycline and which dose, the study allows the treating physician to use daunorubicin at 60 mg or idarubicin at 12 mg.

Elias Jabbour, MD: So, moving forward in the future, you have all these drugs available. How do you sequence them, which one do you choose: quizartinib, sorafenib, or midostaurin?

Harry P. Erba, MD, PhD: Well, let me just say the field is changing very quickly. I think most of us at this table, in a way, expect that midostaurin will get a label in the very near future, at least in the United States. And quite frankly, the QuANTUM-First study will need to be done as an international study because it may be very difficult to randomize patients in the near future in the United States to an arm that does not have a FLT3 inhibitor in it. So, the playing field is going to change when midostaurin comes along and these other drugs will need to be compared. Because, finally, we don’t know why there was a benefit with midostaurin. We assume it’s because it was inhibiting FLT3 mutations, but it also targets other tyrosine kinases, which may be actually very important in the benefit that we saw.

Elias Jabbour, MD: So, Richard, today we have all these tests done. For physicians in the community, should we wait to get all these tests back before we decide on therapy? Let’s say you have somebody with AML. You check for the karyotype, and rule out APL rapidly. But, in order to design, what is the best for the long term? You need to wait to get the FLT3 mutation level, or start chemotherapy and later on catch up and add…

Richard M. Stone, MD: We’re talking about a patient who I think is going to get 3+7 based induction chemotherapy right now. So, in that scenario, at the moment, you don’t have to wait to treat the patient, even when midostaurin becomes available, as Harry just said, since the drug isn’t due to start based on the RATIFY trial until day 8. The only problem with that is you might make the patient ineligible for other clinical trials, should they be available, with other agents. Nonetheless, as a community doctor, you can certainly start the patient and wait for the results, or you should get them back within a week. Obviously, you’ll need to know by that point of time.

Transcript Edited for Clarity
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