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Data Supporting Quizartinib in FLT3+ R/R AML

Panelists: Harry Erba, MD, PhD, Duke University; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, MS, Hospital of The University of Pennsylvania; Daniel Pollyea, MD, MS, University of Colorado, Anschutz Medical Campus; Eunice Wang, MD, Roswell Park Comprehensive Cancer Center
Published: Tuesday, Sep 03, 2019



Transcript: 

Harry Erba, MD, PhD: So let’s turn now to quizartinib. Quizartinib is also a second-generation drug, more specific than the first generation, but it’s a type 2 inhibitor that actually maintains the inactive conformation of the enzyme, but unfortunately the TKD actually favors the active conformation. So TKDs are not susceptible to quizartinib. On the other hand, as I remember your presentation and publication of the phase I data with quizartinib, in patients with low allelic burden of FLT3, there was still activity of quizartinib there as well. But tell us about how quizartinib is being assessed in this population.

Jorge E. Cortes, MD: Yeah, so as you mentioned, this is a drug that has been under development for a few year[s], and it’s gone through different steps including the identification of the appropriate dose because the initial phase I study suggested an MTD [maximum tolerated dose] of 200 mg daily, and then after we went to phase II, we quickly realized that that was too much, mostly because the QTc prolongation. So from there were a couple of studies that brought down to the dose of 30 to 60 mg daily. And the efficacy was very good, very sustained across all these different doses, so we didn’t lose anything in terms of…CRs [complete remission] and CRis [complete remission with incomplete hematologic recovery] across these different doses. But the incidence of QTc prolongation dropped dramatically: with 200 [mg daily] in phase II we saw about 90% of patients with that prolongation, and that went down to single digits when we did the…lower doses.

So these lower doses were the ones that were taken to a randomized study called the QuANTUM-R study [An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive] that was presented last year at EHA [European Hematology Association]; [that] was the first time we presented the data. And the design is very similar to the ADMIRAL study [A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation] that Sasha mentioned, [with] a few differences. The patients were in refractory/relapsed AML. They all had to have FLT3. Only FLT3-ITD was eligible for the study because of the type 2 nature of this inhibitor.… Patients should have received intensive chemotherapy and anthracycline-containing regimen. They…were not eligible if the[y] only had hypomethylating agent or something like that. And if they had a relapse, they had to have relapse within 6 months.

They were randomized 2 to 1 to receive quizartinib, and the way the quizartinib was administered [was] to start with 30 mg for 2 weeks. If the QTc remain[ed] within acceptable limits (480 or less), then they would escalate to 60 mg and then continue uninterrupted until progression.

For the patients who were randomized to the control arm, they could get 1 of 3 salvage therapies, pretty much…the same two intensive [therapies], FLAG [fludarabine, cytarabine, and filgrastim] and MEK [inhibitor]. The nonintensive [therapy option] was low-dose ara-C [cytarabine]. There was no hypomethylating agent control here, and they would receive that as per standard therapy. Patients could receive a transplant and patients who [underwent transplantation], if they were on quizartinib they could go back to quizartinib.

The…control specific therapy…was selected prior to randomization. You had to decide which one you would use.

The primary endpoint was overall survival, and the primary endpoint was met. There was a hazard ratio of 0.76. It was a significant improvement in overall survival. Median survival was prolonged [and] 1-year survival was improved. The response rate, which was a secondary endpoint, CRs and CRis—what was called the composite CR rate—was significantly better. It was almost 50% with the…quizartinib. The majority of the responses were CRis. They were just 5% or 6% of the CRs. Most of them were actually CRis.

There was an improvement in transfusion requirements. There was a post hoc analysis [in which] we found that about 30% of patients became transfusion-independent.

Event-free survival was also improved. So overall…, the rate of transplantation, again knowing that this is not, as Sasha mentioned, the end of FLT3 relapse, so getting them to transplant in this setting would still be what we would like to do. Over 30% of patients were able to go to a transplant, which was much better than what we got with the chemotherapy, which was reflecting the difference in the response rate, as you can imagine.

In terms of safety, it was fairly safe.… The main adverse events that were seen more frequently with quizartinib were (1) QTc prolongation, although the grade 3 incidence was only 3%. So certainly, again, this dose was very safe in that regard. And…(2) also some instances of these differentiation syndromes. So that’s something that you need to be aware with these drugs that we do see these instances.

Other than that [it is] a fairly safe drug, but there was one of the other differences: quizartinib is very potent. Perhaps even a little bit more potent than gilteritinib. And there’s been a debate [about] whether that may be the reason why we see more CRis than CRs, or even CRhs [partial hematologic recovery] with quizartinib…than with, for example, gilteritinib. You see the c-kit inhibition that’s making more prolonged myelosuppression. So there was a little bit more of that. But overall another very effective drug that essentially does the same thing in a very effective and safe way—oral, outpatient—very good.

Harry Erba, MD, PhD: So on your study, about a quarter of the patients who were randomized to get chemotherapy ended up coming off study and it wasn’t true on the quizartinib. Any idea of what those patients went on to get?

Jorge E. Cortes, MD: About 12%, something like that. So there were some. And of course what happened is by the time the study started we had sorafenib and there were other studies. So a lot of the physicians, or the patients, decided, you know what, I want the FLT3 inhibitor by now, because these patients had not been exposed to a FLT3 inhibitor for the most part.

And we looked, we went back to look at the data and we were not able to collect the data in all of them. But sure enough, many of them went on to receive a FLT3 inhibitor, and others received the same standard chemotherapy, but they said, “If I’m going to standard chemotherapy, I’m not going to do it in the study because it’s more restricted.” You know a study makes you [make] more visits and whate

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: So let’s turn now to quizartinib. Quizartinib is also a second-generation drug, more specific than the first generation, but it’s a type 2 inhibitor that actually maintains the inactive conformation of the enzyme, but unfortunately the TKD actually favors the active conformation. So TKDs are not susceptible to quizartinib. On the other hand, as I remember your presentation and publication of the phase I data with quizartinib, in patients with low allelic burden of FLT3, there was still activity of quizartinib there as well. But tell us about how quizartinib is being assessed in this population.

Jorge E. Cortes, MD: Yeah, so as you mentioned, this is a drug that has been under development for a few year[s], and it’s gone through different steps including the identification of the appropriate dose because the initial phase I study suggested an MTD [maximum tolerated dose] of 200 mg daily, and then after we went to phase II, we quickly realized that that was too much, mostly because the QTc prolongation. So from there were a couple of studies that brought down to the dose of 30 to 60 mg daily. And the efficacy was very good, very sustained across all these different doses, so we didn’t lose anything in terms of…CRs [complete remission] and CRis [complete remission with incomplete hematologic recovery] across these different doses. But the incidence of QTc prolongation dropped dramatically: with 200 [mg daily] in phase II we saw about 90% of patients with that prolongation, and that went down to single digits when we did the…lower doses.

So these lower doses were the ones that were taken to a randomized study called the QuANTUM-R study [An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive] that was presented last year at EHA [European Hematology Association]; [that] was the first time we presented the data. And the design is very similar to the ADMIRAL study [A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation] that Sasha mentioned, [with] a few differences. The patients were in refractory/relapsed AML. They all had to have FLT3. Only FLT3-ITD was eligible for the study because of the type 2 nature of this inhibitor.… Patients should have received intensive chemotherapy and anthracycline-containing regimen. They…were not eligible if the[y] only had hypomethylating agent or something like that. And if they had a relapse, they had to have relapse within 6 months.

They were randomized 2 to 1 to receive quizartinib, and the way the quizartinib was administered [was] to start with 30 mg for 2 weeks. If the QTc remain[ed] within acceptable limits (480 or less), then they would escalate to 60 mg and then continue uninterrupted until progression.

For the patients who were randomized to the control arm, they could get 1 of 3 salvage therapies, pretty much…the same two intensive [therapies], FLAG [fludarabine, cytarabine, and filgrastim] and MEK [inhibitor]. The nonintensive [therapy option] was low-dose ara-C [cytarabine]. There was no hypomethylating agent control here, and they would receive that as per standard therapy. Patients could receive a transplant and patients who [underwent transplantation], if they were on quizartinib they could go back to quizartinib.

The…control specific therapy…was selected prior to randomization. You had to decide which one you would use.

The primary endpoint was overall survival, and the primary endpoint was met. There was a hazard ratio of 0.76. It was a significant improvement in overall survival. Median survival was prolonged [and] 1-year survival was improved. The response rate, which was a secondary endpoint, CRs and CRis—what was called the composite CR rate—was significantly better. It was almost 50% with the…quizartinib. The majority of the responses were CRis. They were just 5% or 6% of the CRs. Most of them were actually CRis.

There was an improvement in transfusion requirements. There was a post hoc analysis [in which] we found that about 30% of patients became transfusion-independent.

Event-free survival was also improved. So overall…, the rate of transplantation, again knowing that this is not, as Sasha mentioned, the end of FLT3 relapse, so getting them to transplant in this setting would still be what we would like to do. Over 30% of patients were able to go to a transplant, which was much better than what we got with the chemotherapy, which was reflecting the difference in the response rate, as you can imagine.

In terms of safety, it was fairly safe.… The main adverse events that were seen more frequently with quizartinib were (1) QTc prolongation, although the grade 3 incidence was only 3%. So certainly, again, this dose was very safe in that regard. And…(2) also some instances of these differentiation syndromes. So that’s something that you need to be aware with these drugs that we do see these instances.

Other than that [it is] a fairly safe drug, but there was one of the other differences: quizartinib is very potent. Perhaps even a little bit more potent than gilteritinib. And there’s been a debate [about] whether that may be the reason why we see more CRis than CRs, or even CRhs [partial hematologic recovery] with quizartinib…than with, for example, gilteritinib. You see the c-kit inhibition that’s making more prolonged myelosuppression. So there was a little bit more of that. But overall another very effective drug that essentially does the same thing in a very effective and safe way—oral, outpatient—very good.

Harry Erba, MD, PhD: So on your study, about a quarter of the patients who were randomized to get chemotherapy ended up coming off study and it wasn’t true on the quizartinib. Any idea of what those patients went on to get?

Jorge E. Cortes, MD: About 12%, something like that. So there were some. And of course what happened is by the time the study started we had sorafenib and there were other studies. So a lot of the physicians, or the patients, decided, you know what, I want the FLT3 inhibitor by now, because these patients had not been exposed to a FLT3 inhibitor for the most part.

And we looked, we went back to look at the data and we were not able to collect the data in all of them. But sure enough, many of them went on to receive a FLT3 inhibitor, and others received the same standard chemotherapy, but they said, “If I’m going to standard chemotherapy, I’m not going to do it in the study because it’s more restricted.” You know a study makes you [make] more visits and whate

Transcript Edited for Clarity
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