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Targeting FLT3 in Patients with Relapsed/Refractory 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: Well let’s move on. Let’s talk about targeting FLT3. Now we know that in April of 2017 midostaurin was approved [on the basis of] the results of the RATIFY trial [A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)] published by our colleague Richard M. Stone [MD] in the New England Journal [of Medicine]. [In this trial,] patients who were…59 years and younger with a FLT3-ITD [internal tandem duplication] or [FLT3-]TKD mutation were given midostaurin or placebo in combination with standard chemo[therapy] and consolidation, and then randomization, [and the] same randomization was maintained for a maintenance, and there was a survival benefit. At 4 years, 51% of patients were still alive with midostaurin compared to 44% with just standard 7 and 3…in HiDAC [high-dose cytarabine] with the placebo.

And, again, landmark analysis showed that patients who went on to transplant in first remission after the midostaurin, from the midostaurin arm, had a better overall survival than patients who went on to transplant after just 7 and 3 with placebo. So, again, [it is] very important to be checking [polymerase chain reaction data] for FLT3-ITD and FLT3-TKD for incorporation of this first-generation type 1 inhibitor.

But we have new drugs that are either [recently] approved or on the cusp of hopefully being approved for a [patient with] relapsed-refractory [AML] with FLT3. I’m going to turn to Sasha to talk to us about the development of gilteritinib for relapsed-refractory FLT3-mutated AML.

Alexander E. Perl, MD, MS: So I’m happy to do that, although it’s hard to comment on gilteritinib until we talk about some of the earlier drugs that target FLT3 such as sorafenib [tosylate] [and] quizartinib, because these were earlier drugs that were developed that had activity by acting on FLT3-ITD, and we actually saw that this was a target that we could use drugs that had significant inhibitory potential against as single agents or in combination with low-intensity chemotherapy such as azacitidine. Whereas drugs like midostaurin as a single agent really had very limited activity in the relapsed-refractory setting by themselves.

But one problem that had been noted with the development of sorafenib and quizartinib was that we would see resistance that would develop during therapy [as a result of] treatment-emergent mutations in the tyrosine kinase domain, the DA35. So there was a lot of interest in drugs that would hit both mutations—FLT3-ITD and FLT3-TKDs. And that’s where gilteritinib came from.

So gilteritinib is a relatively selective and potent FLT3 inhibitor that’s active against both these mutations by virtue that it is a type 1 inhibitor, and it underwent a phase I/II study that showed [that] about 40% to 50% of patients with relapsed or refractory FLT3-mutated AML would achieve…elimination of their bone marrow blast or near elimination of bone marrow blast with variable count recovery. And some patients would actually achieve a true CR [complete remission]. About 10% to 20% of patients would go to either transfusion independence or full count recovery, indicating a significant amount of recovery of hematopoiesis, which really [hasn’t] been seen with some of the other FLT3 inhibitors as single agent.

And then a randomized study followed where gilteritinib as a single agent was compared to…best available chemotherapy for patients in first relapse or with primary refractory disease. This was a study that enrolled over 370 patients. They had to have [been] previously treated, although they did not have to have [had] previous intensive chemotherapy.… They had to have a FLT3 mutation because the prior studies in the phase I/II setting really showed very limited activity in patients who didn’t have the target mutation.

So we had to prove at the time of relapse that they had a FLT3-ITD or a FLT3-TKD mutation. And then [the patients] were randomized 2 to 1 to either gilteritinib as a single agent or the investigator’s choice of 1 of 4 regimens, 2 of which were intensive, Flag-IDA [fludarabine, cytarabine, granulocyte colony stimulating factor, and idarubicin] [and] MEK [inhibitor], and 2 of which were low intensity, azacitidine [and] low-dose cytarabine. And that decision had to be made prior to randomization. So you couldn’t get the randomization and then figure out what you wanted from the list; you had to lock in before randomization. Then they were followed for overall survival.

What the study showed was that there was a higher response rate in the gilteritinib arm, and as well, recently presented, was that there was a better survival in the gilteritinib arm with a median overall survival [of] 9.3 months, and median overall survival of 5.6 months in the chemotherapy arm. That was statistically significantly improved.

There was also higher rate of transplantation in the gilteritinib arm. And when we looked also at the patients who went to transplant, those patients were allowed to go back on gilteritinib after engraftment, and they had some of the best survival [in] the study.              

So the take-home from this is that we’ve shown in a randomized study that in the FLT3-mutated population, there’s a survival benefit to using once-daily oral FLT3 inhibitor. You may ask what’s the toxicity comparison here. The big difference is where you give the therapy, which is this is a once-a-day pill with relatively few [adverse] effects outside of cytopenias, which are quite common, [and] LFT [liver function test] abnormalities, which are usually asymptomatic. And while there were serious [adverse] effects, they were pretty rare. So we did see rare cases where there was PRES, posterior reversible encephalopathy. Cases of pancreatitis…happened in a small number of patients but could be severe. And there were a few cases of differentiation syndrome or something that was similar to differentiation syndrome.

In terms of fevers that are relatively common, we would see in some patients pulmonary infiltrates that were not clearly infectious—fluid retention. And while this is certainly not in the order of frequency that we see the IDH [isocitrate dehydrogenase] inhibitors, it has been recognized and it is a black box warning on the label. The drug was approved initially and within the past week that label has actually been expanded to include the overall survival data.

So we have a new drug in the setting for relapsed and refractory patients, and it’s a nice addition to the armamentarium. But one real important thing to take home from this is [that] while we’re seeing improved survival, I can’t say this problem is fixed. We are seeing patients who respond to the drug and then progress. And the overall survival for the study population as a whole, if you follow them for several years, it really does drop down quite low. So the best way to develop these drugs I think is by moving to front line, and those studies are ongoing.

Harry Erba, MD, PhD: So how is it being looked at? Where is the study being looked at front line?

Alexander E. Perl, MD, MS: So there’s already been a phase I/II study that has looked at combinations of 7 and 3 plus gilteritinib for various different anthracycline combinations and also durations of gilteritinib in different doses. That study is basically completed and the precog [prediction of clinical outcomes from genomic profiles] is going to be looking at comparing gilteritinib added to front-line intensive 7 and 3, and IDAC [intermediate-dose ara-C (cytarabine)] to midostaurin added, as is the current standard of care. And a similar study is going on in Europe.

And there are other FLT3 inhibitors that are undergoing front-line development. Quizartinib is undergoing front-line development in a similar kind of setting; it’s placebo controlled. And crenolanib, which is another type 1 inhibitor, is being compared to midostaurin in very similar kind of study like I described.

Harry Erba, MD, PhD: Yeah, if we have time maybe I’ll ask Eunice about the crenolanib data. She presented a very controversial abstract as I remember at ASH [American Society of Hematology] a couple of years ago that got us, got me thinking about the development of that drug as well.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: Well let’s move on. Let’s talk about targeting FLT3. Now we know that in April of 2017 midostaurin was approved [on the basis of] the results of the RATIFY trial [A Phase III Randomized, Double-Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) (IND #101261) or Placebo in Newly Diagnosed Patients < 60 Years of Age With FLT3 Mutated Acute Myeloid Leukemia (AML)] published by our colleague Richard M. Stone [MD] in the New England Journal [of Medicine]. [In this trial,] patients who were…59 years and younger with a FLT3-ITD [internal tandem duplication] or [FLT3-]TKD mutation were given midostaurin or placebo in combination with standard chemo[therapy] and consolidation, and then randomization, [and the] same randomization was maintained for a maintenance, and there was a survival benefit. At 4 years, 51% of patients were still alive with midostaurin compared to 44% with just standard 7 and 3…in HiDAC [high-dose cytarabine] with the placebo.

And, again, landmark analysis showed that patients who went on to transplant in first remission after the midostaurin, from the midostaurin arm, had a better overall survival than patients who went on to transplant after just 7 and 3 with placebo. So, again, [it is] very important to be checking [polymerase chain reaction data] for FLT3-ITD and FLT3-TKD for incorporation of this first-generation type 1 inhibitor.

But we have new drugs that are either [recently] approved or on the cusp of hopefully being approved for a [patient with] relapsed-refractory [AML] with FLT3. I’m going to turn to Sasha to talk to us about the development of gilteritinib for relapsed-refractory FLT3-mutated AML.

Alexander E. Perl, MD, MS: So I’m happy to do that, although it’s hard to comment on gilteritinib until we talk about some of the earlier drugs that target FLT3 such as sorafenib [tosylate] [and] quizartinib, because these were earlier drugs that were developed that had activity by acting on FLT3-ITD, and we actually saw that this was a target that we could use drugs that had significant inhibitory potential against as single agents or in combination with low-intensity chemotherapy such as azacitidine. Whereas drugs like midostaurin as a single agent really had very limited activity in the relapsed-refractory setting by themselves.

But one problem that had been noted with the development of sorafenib and quizartinib was that we would see resistance that would develop during therapy [as a result of] treatment-emergent mutations in the tyrosine kinase domain, the DA35. So there was a lot of interest in drugs that would hit both mutations—FLT3-ITD and FLT3-TKDs. And that’s where gilteritinib came from.

So gilteritinib is a relatively selective and potent FLT3 inhibitor that’s active against both these mutations by virtue that it is a type 1 inhibitor, and it underwent a phase I/II study that showed [that] about 40% to 50% of patients with relapsed or refractory FLT3-mutated AML would achieve…elimination of their bone marrow blast or near elimination of bone marrow blast with variable count recovery. And some patients would actually achieve a true CR [complete remission]. About 10% to 20% of patients would go to either transfusion independence or full count recovery, indicating a significant amount of recovery of hematopoiesis, which really [hasn’t] been seen with some of the other FLT3 inhibitors as single agent.

And then a randomized study followed where gilteritinib as a single agent was compared to…best available chemotherapy for patients in first relapse or with primary refractory disease. This was a study that enrolled over 370 patients. They had to have [been] previously treated, although they did not have to have [had] previous intensive chemotherapy.… They had to have a FLT3 mutation because the prior studies in the phase I/II setting really showed very limited activity in patients who didn’t have the target mutation.

So we had to prove at the time of relapse that they had a FLT3-ITD or a FLT3-TKD mutation. And then [the patients] were randomized 2 to 1 to either gilteritinib as a single agent or the investigator’s choice of 1 of 4 regimens, 2 of which were intensive, Flag-IDA [fludarabine, cytarabine, granulocyte colony stimulating factor, and idarubicin] [and] MEK [inhibitor], and 2 of which were low intensity, azacitidine [and] low-dose cytarabine. And that decision had to be made prior to randomization. So you couldn’t get the randomization and then figure out what you wanted from the list; you had to lock in before randomization. Then they were followed for overall survival.

What the study showed was that there was a higher response rate in the gilteritinib arm, and as well, recently presented, was that there was a better survival in the gilteritinib arm with a median overall survival [of] 9.3 months, and median overall survival of 5.6 months in the chemotherapy arm. That was statistically significantly improved.

There was also higher rate of transplantation in the gilteritinib arm. And when we looked also at the patients who went to transplant, those patients were allowed to go back on gilteritinib after engraftment, and they had some of the best survival [in] the study.              

So the take-home from this is that we’ve shown in a randomized study that in the FLT3-mutated population, there’s a survival benefit to using once-daily oral FLT3 inhibitor. You may ask what’s the toxicity comparison here. The big difference is where you give the therapy, which is this is a once-a-day pill with relatively few [adverse] effects outside of cytopenias, which are quite common, [and] LFT [liver function test] abnormalities, which are usually asymptomatic. And while there were serious [adverse] effects, they were pretty rare. So we did see rare cases where there was PRES, posterior reversible encephalopathy. Cases of pancreatitis…happened in a small number of patients but could be severe. And there were a few cases of differentiation syndrome or something that was similar to differentiation syndrome.

In terms of fevers that are relatively common, we would see in some patients pulmonary infiltrates that were not clearly infectious—fluid retention. And while this is certainly not in the order of frequency that we see the IDH [isocitrate dehydrogenase] inhibitors, it has been recognized and it is a black box warning on the label. The drug was approved initially and within the past week that label has actually been expanded to include the overall survival data.

So we have a new drug in the setting for relapsed and refractory patients, and it’s a nice addition to the armamentarium. But one real important thing to take home from this is [that] while we’re seeing improved survival, I can’t say this problem is fixed. We are seeing patients who respond to the drug and then progress. And the overall survival for the study population as a whole, if you follow them for several years, it really does drop down quite low. So the best way to develop these drugs I think is by moving to front line, and those studies are ongoing.

Harry Erba, MD, PhD: So how is it being looked at? Where is the study being looked at front line?

Alexander E. Perl, MD, MS: So there’s already been a phase I/II study that has looked at combinations of 7 and 3 plus gilteritinib for various different anthracycline combinations and also durations of gilteritinib in different doses. That study is basically completed and the precog [prediction of clinical outcomes from genomic profiles] is going to be looking at comparing gilteritinib added to front-line intensive 7 and 3, and IDAC [intermediate-dose ara-C (cytarabine)] to midostaurin added, as is the current standard of care. And a similar study is going on in Europe.

And there are other FLT3 inhibitors that are undergoing front-line development. Quizartinib is undergoing front-line development in a similar kind of setting; it’s placebo controlled. And crenolanib, which is another type 1 inhibitor, is being compared to midostaurin in very similar kind of study like I described.

Harry Erba, MD, PhD: Yeah, if we have time maybe I’ll ask Eunice about the crenolanib data. She presented a very controversial abstract as I remember at ASH [American Society of Hematology] a couple of years ago that got us, got me thinking about the development of that drug as well.

Transcript Edited for Clarity
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