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Gilteritinib for FLT3-Mutant AML

Panelists: Naval G. Daver, MD, The University of Texas MD Anderson Cancer Center; Harry Erba, MD, PhD, Duke University; Mark J. Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center; Alexander Perl, MD, Abramson Cancer Center, University of Pennsylvania; Raajit K. Rampal, MD, PhD Memorial Sloan Kettering Cancer Center
Published: Wednesday, Feb 13, 2019



Transcript: 

Harry Erba, MD, PhD: So let’s move on then to the more recent approval of gilteritinib for our patients with relapsed and refractory acute myeloid leukemia [AML] with either a FLT3-ITD [internal tandem duplication] or TKD [tyrosine kinase domain]. Sasha, I know you’ve been very much involved in the development of gilteritinib. Why don’t you bring us up to date on that.

Alexander Perl, MD: Well, the biggest update on gilteritinib is that it’s now approved. It was approved based on the interim analysis from a phase III study, the final data of which are not yet publicly available. We hope to have that soon. But the response rate on that study showed that the drug has activity in a very hard-to-treat population that has a very low response rate to salvage chemotherapy. The expected response to chemotherapy was really quite abysmal, so improving that bar even a small amount could be a big gain, ultimately, which we’ll see more on soon when the data are back from that study.  

So this is an active agent. And what’s notable about the approval is that it’s based off CR [complete remission] and CRH [CR with partial hematologic recovery]. It’s not based off CRI [CR with incomplete recovery] or some modification of CRI or anything that was cooked up to make a FLT3 inhibitor look active in the setting with modifications for what could be toxicity of the drug. These are the agreed-upon standard definitions for all agents being looked at by the FDA right now. And it’s only 21%, but it is actually, in this population, a reasonable response rate for what’s, again, going to be associated with a good quality of life for that patient, etc.

Harry Erba, MD, PhD: But let me ask you before you go on about that. We also had the response to the less intensive and more intensive therapy. Why wasn’t that in the label, so a clinician can look at the label and say, “Hey, 21% doesn’t sound so great. But look what it was with chemotherapy.” Why wasn’t it there?

Alexander Perl, MD: What I can say is, stay tuned. I didn’t come up with the physical analysis plan of this study, which had to do with an interim analysis to meet a prespecified endpoint for the trial. There are actually interim analyses of survival on this study as well as a final analysis for survival on this study. We’ll have the data soon. We had hoped to have everything here for ASH [the American Society of Hematology Annual Meeting and Exposition], but the timing doesn’t always work out.

Harry Erba, MD, PhD: You know, remember the lestaurtinib study. That’s when it hit me in the face that in FLT3-relapsed AML, that the response to chemotherapy, we used the MEK [inhibitor] and HiDAC [high-dose cytarabine].

Mark J. Levis, MD, PhD: Fall off the cliff bad.

Harry Erba, MD, PhD: Yeah, it was like 20%. It was just as well, and now you’re talking about an outpatient oral therapy.

Alexander Perl, MD: Right, once a day you take your pill, and generally these patients do pretty well on this drug. It’s got very limited toxicity. I won’t say there’s no toxicity. You certainly see cytopenias with this drug. You do see LFT [liver function test] abnormalities. The label recommends monitoring the QT interval, although I have to say, there’s very minimal QT effect that I have seen personally. And I can only think of rare patients whom we’ve ever had to make dose modification based on QT.

Harry Erba, MD, PhD: So it’s going to be developed in addition to the chemotherapy backbone?

Alexander Perl, MD: Yeah. So the exciting thing about it is, once we saw it was active in the relapsed and refractory setting, right away we went to say, how can we use this in frontline patients? Because nobody wants to treat relapsed AML; you want to prevent relapses. So data on the frontline approach, in which we added a 14-day treatment with gilteritinib to induction chemotherapy, consolidation chemotherapy, and then maintenance. And patients who went on to transplant could get maintenance with the drug after they were presented.

Now in this study, this is a phase I study to look at what the optimal dose is, and a little bit at what the optimal anthracycline and schedule is, so there were patients who were FLT3 wild type, patients who were FLT3 mutated. But we have a lot more data on the FLT3-mutated patients from this study, although most of it is response data. We don’t have a lot of survival data or relapsed rates or things like that, which I would really like to get further analysis on and get those data out there so we can start getting a sense of, how does this stack up to data that we know? But the response rate is extremely high, and virtually all patients responded with 1 cycle. And that was really different from what we saw on RATIFY. And when I say really high, I think the combined CR rates—CR, CRI, CRP [CR with incomplete platelet recovery]—were 93%-plus. So that is, granted, a small phase II setting.

Mark J. Levis, MD, PhD: However, the question is going to be answered. They’re already launching the randomized study against midostaurin.

Alexander Perl, MD: Yeah. And you stole my thunder there. I was going to say the next thing to do… obviously, it wasn’t hard to do it, and we need this in a randomized study.

Harry Erba, MD, PhD: And daunorubicin 90 mg or 60 mg in the study?

Alexander Perl, MD: I think it depends on where you’re studying it. Two studies. There’s going to be a US study, and there’s going to be a European study.

Mark J. Levis, MD, PhD: It’s malpractice if you don’t give anthracycline X.

Harry Erba, MD, PhD: So remember that the midostaurin study was based on some preclinical data—actually from you, I think, about the sequence of a FLT3 inhibitor best given after chemotherapy. But in this study, it stays as days 4 through 17, is that right?

Alexander Perl, MD: We wrote the regimen. It actually initially was concurrent and that wasn’t well tolerated. It quickly moved to the FLT3 inhibitor after the daunorubicin. It was actually after the idarubicin was done. That was 4 to 17. And then we’ve matched it to what’s done in RATIFY. So 8 to 25.

Harry Erba, MD, PhD: So direct insight into this then.

Mark J. Levis, MD, PhD: Yes. There are data suggesting sequencing when the preclinical data set, if you give your FLT3 inhibitor during or after chemotherapy, was synergistic. If you gave it well before, it actually would put cells into cell-cycle rest, and they wouldn’t respond to chemotherapy. So the designers of the RATIFY trial sort of interpreted this not the way I would have. They said, “We have to do it after.” And I said, “No, you can actually do it during. In fact, it kind of makes more sense, but you have to avoid the anthracycline.”

And so we thought they would start on day 4. Instead, they started on day 8. Part of that was just tolerability. They tried on day 4, and patients couldn’t tolerate it. But gilteritinib, because you can take gilteritinib and not know it’s the same as placebo, you will not know you’re taking it. You can take that on day 4. And so that allows us to go back in history and say, “No, that was the way we wanted to do it originally.” However, to imitate RATIFY, there is this push to do it on day 8 for reasons that I would point out are flawed, because RATIFY was doing it wrong in the first place. If they could have, they would have wanted to do it on day 4. And they tried, as you recall.

Alexander Perl, MD: I think it may affect interpretation nadir. Marrows make certain things a little bit challenging.

Naval G. Daver, MD: One of the things in the approved indication with gilteritinib that I think is very important is that there is actually a randomized study that shows CR response rates in FLT3-mutated relapse, which is QuANTUM-R. And of course these are different studies. But I was shocked to see the CR rate was 1%. And I think the CR and CRI even together is 23%, 24%. And that’s CRI. So I think even though we don’t know, and we hopefully will know, I think a CR, CRH with a single agent is good. And I think we were a little bit spoiled in AML. You know, all the excitement with PD-1 [programmed cell death protein 1] inhibitors and solid tumors? What’s the response rate, 15%, 18%? Lung cancer. Now, of course, you combine them, and that’s what we should do. So we showed some data with quizartinib, azacitidine with quizartinib, versus quizartinib alone.

And in the salvage setting we’re seeing the response rates are high in survival, but I don’t think anybody is surprised. We just had to do it; we did it. But you go from the 6 months to 12, 14 months. So I think we need these tools; they’re out there. Now the real research begins. How do you combine them? How do you sequence them?

Harry Erba, MD, PhD: How about the quality of the remissions with gilteritinib? You presented data on MRD [minimal residual disease] in the relapsed/refractory setting.

Mark J. Levis, MD, PhD: Those actually were kind of surprising. And again, gilteritinib is unique. It does not inhibit c-Kit. You don’t get the myelosuppression. You don’t get the requirement for transfusions. And when we applied a novel assay combining PCR [polymerase chain reaction] next-generation sequencingone which actually is available; you can order it—that assay identified patients who had a remission and were MRD negative. And lo and behold, they lived a lot longer than the patients who had remissions who were MRD positive. Furthermore, the quality of response, a CR/CRH, had a higher rate of being MRD negative than the other responses. So everything goes together. We’re going to use MRD to actually kind of characterize these funny responses.

Harry Erba, MD, PhD: Some people would consider anything that has a subscript after CR as being a less important CR. What did you notice about MRD with CRH?

Mark J. Levis, MD, PhD: I would actually sort of agree with that. CRH is very close to a CR; it really is. Again, you can go to the Bahamas with a CRH.

Harry Erba, MD, PhD: That’s right, an arbitrary cutoff.

Mark J. Levis, MD, PhD: Yeah. I’ve heard someone say, “These patients are swimming to the Bahamas because they’ve got a CRH.” No, that was actually fairly reassuring to see the combination of CR, CRH had such a high MRD-negative rate. And so, no, I think when we say a CRH, the MRD reassures us in that regard.

Alexander Perl, MD: But I do think we have to be careful calling the MRD negativity in a drug that works very differently from cytotoxic chemotherapy. Because we’re looking for a mutation, we’re not looking for flow evidence of a leukemia cell. And there were patients who actually didn’t meet criteria for CR who yet were MRD negative. Now what’s going on in that marrow? Is that clonal rearrangement for cells that don’t have a FLT3 mutation? I think that takes further study.

Mark J. Levis, MD, PhD: In those cases, I think we cleared the FLT3 clone and the rest of the chemotherapy appears...

Alexander Perl, MD: Probably that’s more indolent, and that’s where the combinations may be, you know…

Naval G. Daver, MD: But I think for community, I think you’re right. The MRD is nice. But they say, what are you going do with IDH and FLT3. If the MRD is negative, I high-five the patient. Because everything else goes on. You treat them the same. You don’t stop treatment. You don’t intensify treatment. So it’s nice, and it makes you feel good, but today we don’t change any treatment.

Mark J. Levis, MD, PhD: We will know with MRD with the results of randomized trials that are ongoing now.

Raajit K. Rampal, MD, PhD: Could you stop?

Mark J. Levis, MD, PhD: I think we’re going to get an answer. Not just could we stop. We’re checking MRD at multiple stages, and diagnosis all the way out to maintenance to really find out—with a good assay. Now this applies only to FLT3. We really need to do this sort of thing for all of AML. We need to expand it for the rest of AML if we can.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: So let’s move on then to the more recent approval of gilteritinib for our patients with relapsed and refractory acute myeloid leukemia [AML] with either a FLT3-ITD [internal tandem duplication] or TKD [tyrosine kinase domain]. Sasha, I know you’ve been very much involved in the development of gilteritinib. Why don’t you bring us up to date on that.

Alexander Perl, MD: Well, the biggest update on gilteritinib is that it’s now approved. It was approved based on the interim analysis from a phase III study, the final data of which are not yet publicly available. We hope to have that soon. But the response rate on that study showed that the drug has activity in a very hard-to-treat population that has a very low response rate to salvage chemotherapy. The expected response to chemotherapy was really quite abysmal, so improving that bar even a small amount could be a big gain, ultimately, which we’ll see more on soon when the data are back from that study.  

So this is an active agent. And what’s notable about the approval is that it’s based off CR [complete remission] and CRH [CR with partial hematologic recovery]. It’s not based off CRI [CR with incomplete recovery] or some modification of CRI or anything that was cooked up to make a FLT3 inhibitor look active in the setting with modifications for what could be toxicity of the drug. These are the agreed-upon standard definitions for all agents being looked at by the FDA right now. And it’s only 21%, but it is actually, in this population, a reasonable response rate for what’s, again, going to be associated with a good quality of life for that patient, etc.

Harry Erba, MD, PhD: But let me ask you before you go on about that. We also had the response to the less intensive and more intensive therapy. Why wasn’t that in the label, so a clinician can look at the label and say, “Hey, 21% doesn’t sound so great. But look what it was with chemotherapy.” Why wasn’t it there?

Alexander Perl, MD: What I can say is, stay tuned. I didn’t come up with the physical analysis plan of this study, which had to do with an interim analysis to meet a prespecified endpoint for the trial. There are actually interim analyses of survival on this study as well as a final analysis for survival on this study. We’ll have the data soon. We had hoped to have everything here for ASH [the American Society of Hematology Annual Meeting and Exposition], but the timing doesn’t always work out.

Harry Erba, MD, PhD: You know, remember the lestaurtinib study. That’s when it hit me in the face that in FLT3-relapsed AML, that the response to chemotherapy, we used the MEK [inhibitor] and HiDAC [high-dose cytarabine].

Mark J. Levis, MD, PhD: Fall off the cliff bad.

Harry Erba, MD, PhD: Yeah, it was like 20%. It was just as well, and now you’re talking about an outpatient oral therapy.

Alexander Perl, MD: Right, once a day you take your pill, and generally these patients do pretty well on this drug. It’s got very limited toxicity. I won’t say there’s no toxicity. You certainly see cytopenias with this drug. You do see LFT [liver function test] abnormalities. The label recommends monitoring the QT interval, although I have to say, there’s very minimal QT effect that I have seen personally. And I can only think of rare patients whom we’ve ever had to make dose modification based on QT.

Harry Erba, MD, PhD: So it’s going to be developed in addition to the chemotherapy backbone?

Alexander Perl, MD: Yeah. So the exciting thing about it is, once we saw it was active in the relapsed and refractory setting, right away we went to say, how can we use this in frontline patients? Because nobody wants to treat relapsed AML; you want to prevent relapses. So data on the frontline approach, in which we added a 14-day treatment with gilteritinib to induction chemotherapy, consolidation chemotherapy, and then maintenance. And patients who went on to transplant could get maintenance with the drug after they were presented.

Now in this study, this is a phase I study to look at what the optimal dose is, and a little bit at what the optimal anthracycline and schedule is, so there were patients who were FLT3 wild type, patients who were FLT3 mutated. But we have a lot more data on the FLT3-mutated patients from this study, although most of it is response data. We don’t have a lot of survival data or relapsed rates or things like that, which I would really like to get further analysis on and get those data out there so we can start getting a sense of, how does this stack up to data that we know? But the response rate is extremely high, and virtually all patients responded with 1 cycle. And that was really different from what we saw on RATIFY. And when I say really high, I think the combined CR rates—CR, CRI, CRP [CR with incomplete platelet recovery]—were 93%-plus. So that is, granted, a small phase II setting.

Mark J. Levis, MD, PhD: However, the question is going to be answered. They’re already launching the randomized study against midostaurin.

Alexander Perl, MD: Yeah. And you stole my thunder there. I was going to say the next thing to do… obviously, it wasn’t hard to do it, and we need this in a randomized study.

Harry Erba, MD, PhD: And daunorubicin 90 mg or 60 mg in the study?

Alexander Perl, MD: I think it depends on where you’re studying it. Two studies. There’s going to be a US study, and there’s going to be a European study.

Mark J. Levis, MD, PhD: It’s malpractice if you don’t give anthracycline X.

Harry Erba, MD, PhD: So remember that the midostaurin study was based on some preclinical data—actually from you, I think, about the sequence of a FLT3 inhibitor best given after chemotherapy. But in this study, it stays as days 4 through 17, is that right?

Alexander Perl, MD: We wrote the regimen. It actually initially was concurrent and that wasn’t well tolerated. It quickly moved to the FLT3 inhibitor after the daunorubicin. It was actually after the idarubicin was done. That was 4 to 17. And then we’ve matched it to what’s done in RATIFY. So 8 to 25.

Harry Erba, MD, PhD: So direct insight into this then.

Mark J. Levis, MD, PhD: Yes. There are data suggesting sequencing when the preclinical data set, if you give your FLT3 inhibitor during or after chemotherapy, was synergistic. If you gave it well before, it actually would put cells into cell-cycle rest, and they wouldn’t respond to chemotherapy. So the designers of the RATIFY trial sort of interpreted this not the way I would have. They said, “We have to do it after.” And I said, “No, you can actually do it during. In fact, it kind of makes more sense, but you have to avoid the anthracycline.”

And so we thought they would start on day 4. Instead, they started on day 8. Part of that was just tolerability. They tried on day 4, and patients couldn’t tolerate it. But gilteritinib, because you can take gilteritinib and not know it’s the same as placebo, you will not know you’re taking it. You can take that on day 4. And so that allows us to go back in history and say, “No, that was the way we wanted to do it originally.” However, to imitate RATIFY, there is this push to do it on day 8 for reasons that I would point out are flawed, because RATIFY was doing it wrong in the first place. If they could have, they would have wanted to do it on day 4. And they tried, as you recall.

Alexander Perl, MD: I think it may affect interpretation nadir. Marrows make certain things a little bit challenging.

Naval G. Daver, MD: One of the things in the approved indication with gilteritinib that I think is very important is that there is actually a randomized study that shows CR response rates in FLT3-mutated relapse, which is QuANTUM-R. And of course these are different studies. But I was shocked to see the CR rate was 1%. And I think the CR and CRI even together is 23%, 24%. And that’s CRI. So I think even though we don’t know, and we hopefully will know, I think a CR, CRH with a single agent is good. And I think we were a little bit spoiled in AML. You know, all the excitement with PD-1 [programmed cell death protein 1] inhibitors and solid tumors? What’s the response rate, 15%, 18%? Lung cancer. Now, of course, you combine them, and that’s what we should do. So we showed some data with quizartinib, azacitidine with quizartinib, versus quizartinib alone.

And in the salvage setting we’re seeing the response rates are high in survival, but I don’t think anybody is surprised. We just had to do it; we did it. But you go from the 6 months to 12, 14 months. So I think we need these tools; they’re out there. Now the real research begins. How do you combine them? How do you sequence them?

Harry Erba, MD, PhD: How about the quality of the remissions with gilteritinib? You presented data on MRD [minimal residual disease] in the relapsed/refractory setting.

Mark J. Levis, MD, PhD: Those actually were kind of surprising. And again, gilteritinib is unique. It does not inhibit c-Kit. You don’t get the myelosuppression. You don’t get the requirement for transfusions. And when we applied a novel assay combining PCR [polymerase chain reaction] next-generation sequencingone which actually is available; you can order it—that assay identified patients who had a remission and were MRD negative. And lo and behold, they lived a lot longer than the patients who had remissions who were MRD positive. Furthermore, the quality of response, a CR/CRH, had a higher rate of being MRD negative than the other responses. So everything goes together. We’re going to use MRD to actually kind of characterize these funny responses.

Harry Erba, MD, PhD: Some people would consider anything that has a subscript after CR as being a less important CR. What did you notice about MRD with CRH?

Mark J. Levis, MD, PhD: I would actually sort of agree with that. CRH is very close to a CR; it really is. Again, you can go to the Bahamas with a CRH.

Harry Erba, MD, PhD: That’s right, an arbitrary cutoff.

Mark J. Levis, MD, PhD: Yeah. I’ve heard someone say, “These patients are swimming to the Bahamas because they’ve got a CRH.” No, that was actually fairly reassuring to see the combination of CR, CRH had such a high MRD-negative rate. And so, no, I think when we say a CRH, the MRD reassures us in that regard.

Alexander Perl, MD: But I do think we have to be careful calling the MRD negativity in a drug that works very differently from cytotoxic chemotherapy. Because we’re looking for a mutation, we’re not looking for flow evidence of a leukemia cell. And there were patients who actually didn’t meet criteria for CR who yet were MRD negative. Now what’s going on in that marrow? Is that clonal rearrangement for cells that don’t have a FLT3 mutation? I think that takes further study.

Mark J. Levis, MD, PhD: In those cases, I think we cleared the FLT3 clone and the rest of the chemotherapy appears...

Alexander Perl, MD: Probably that’s more indolent, and that’s where the combinations may be, you know…

Naval G. Daver, MD: But I think for community, I think you’re right. The MRD is nice. But they say, what are you going do with IDH and FLT3. If the MRD is negative, I high-five the patient. Because everything else goes on. You treat them the same. You don’t stop treatment. You don’t intensify treatment. So it’s nice, and it makes you feel good, but today we don’t change any treatment.

Mark J. Levis, MD, PhD: We will know with MRD with the results of randomized trials that are ongoing now.

Raajit K. Rampal, MD, PhD: Could you stop?

Mark J. Levis, MD, PhD: I think we’re going to get an answer. Not just could we stop. We’re checking MRD at multiple stages, and diagnosis all the way out to maintenance to really find out—with a good assay. Now this applies only to FLT3. We really need to do this sort of thing for all of AML. We need to expand it for the rest of AML if we can.

Transcript Edited for Clarity 
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