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AML: An Overview of Available FTL3 Inhibitors

Insights From: Richard F. Schlenk, MD, University of Ulm; Harry Erba, MD PhD, University of Alabama ; Naval G. Daver, MD, MD Anderson Cancer Center
Published: Thursday, Oct 11, 2018



Transcript: 

Naval G. Daver, MD: There are 5 of the FLT3 inhibitors that are in clinical development. The first generation, or the earlier ones, include sorafenib and midostaurin; these were less potent as single agents. In fact, the single-agent response rates in relapsed AML with both sorafenib and midostaurin are in the range of 5% to 10%, so very modest. However, both of these, when combined with standard induction therapy—whether it was 3+7, FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin], or ADE [cytarabine/daunorubicin/etoposide]—did not show an improvement in response rate, since it was already relatively good in FLT3 ITD [internal tandem duplication]-mutated patients with standard induction alone. But they did improve the relapse-free survival and the overall survival.  

These drugs have been tried in combination with induction therapy. The largest study, which is a phase III study called the RATIFY study, used the combination of 3+7, which is standard induction with midostaurin, versus 3+7 in combination with placebo. The findings included the combination of 3+7 with the addition of the first-generation FLT3 inhibitor, midostaurin, resulting in the improvement of overall survival, which is a primary endpoint. This resulted in the phase III trial and FDA approval of this agent.

There have also been studies using sorafenib in combination with the induction chemotherapy, both from our group at MD Anderson and our German colleagues, which have shown that the addition of sorafenib to induction therapy does seem to improve event-free survival; this was seen in both FLT3-mutated as well as FLT3 wild-type disease. So there is now a new stream of thought that a lot of these FLT3 inhibitors—because they inhibit many pathways including FLT3, KIT, RAF, AXL, RAS, and VEGF—may actually have an impact, definitely in the FLT3 ITD-mutated AML, but also in FLT3 wild-type disease.

There are 3 new second-generation FLT3 inhibitors, which are just more modern, but they’re also more potent as single agents. These include 3 drugs: quizartinib, gilteritinib, and crenolanib. The first 2 are the ones that are advanced in clinical development in phase III studies, which were done this time with single-agent quizartinib and single-agent gilteritinib in relapsed/refractory acute myeloid leukemia. Furthermore, both of these studies have completed accrual.

The quizartinib phase III trial was a late-breaker at the EHA [European Hematology Association] meeting a couple of months ago in June, which showed that quizartinib, as single-agent therapy, did show an improvement in survival over standard therapies that the treating physicians gave. This was the primary endpoint, which has been met, so we expect quizartinib will be approved as a single agent in relapsed/refractory FLT3 ITD AML.

Gilteritinib also has a similar phase III trial in first-relapse FLT3 ITD and FLT3 D835 AML. The data have not yet been released, but we do know they have filed with the FDA, so we are expecting that both quizartinib and gilteritinib will become available probably by the end of 2018 or early 2019. This will give us many more options, in addition to sorafenib and midostaurin, for patients with FLT3-mutated AML.

Richard F. Schlenk, MD: There are 2 types of second-generation inhibitors, and gilteritinib and crenolanib are type 1. They inhibit the active and inactive FLT3 receptor kinase, whereas the type 2 inhibitor, quizartinib, only inhibits the inactive form of FLT3.

The second-generation inhibitors differ in half-life, which is quite important because, for example, quizartinib and gilteritinib have to be applied only once daily whereas crenolanib has to be applied 3 times daily. So you see there is a great difference in half-life, and there are some advantages for quizartinib and gilteritinib in that they have to be taken only once daily. However, if there are clinical problems—as we have already seen in acute myeloid leukemia patients—crenolanib may be preferable because it can be easily put off and the half-life is very short. The effect of the drug is very limited in time.

Resistance to second-generation FLT3 inhibitors can arise with new mutations. For example, patients have been identified with FLT3 internal tandem duplication, who have been treated with quizartinib. As a resistant mechanism, an FLT3 tyrosine kinase domain mutation came up; this is one mechanism to develop resistance to, for example, quizartinib. There are other mutations that can occur as point mutations in FLT3, but otherwise, AML is a clonal disease. Therefore, sometimes relapses or resistances to specific inhibitors come from other clones that are not related to FLT3. For example, sometimes we are able to inhibit the clone that is FLT3 mutation-positive, after which another clone arises, yielding a disease resistant to the FLT3 inhibitor.

Transcript Edited for Clarity 
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Transcript: 

Naval G. Daver, MD: There are 5 of the FLT3 inhibitors that are in clinical development. The first generation, or the earlier ones, include sorafenib and midostaurin; these were less potent as single agents. In fact, the single-agent response rates in relapsed AML with both sorafenib and midostaurin are in the range of 5% to 10%, so very modest. However, both of these, when combined with standard induction therapy—whether it was 3+7, FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin], or ADE [cytarabine/daunorubicin/etoposide]—did not show an improvement in response rate, since it was already relatively good in FLT3 ITD [internal tandem duplication]-mutated patients with standard induction alone. But they did improve the relapse-free survival and the overall survival.  

These drugs have been tried in combination with induction therapy. The largest study, which is a phase III study called the RATIFY study, used the combination of 3+7, which is standard induction with midostaurin, versus 3+7 in combination with placebo. The findings included the combination of 3+7 with the addition of the first-generation FLT3 inhibitor, midostaurin, resulting in the improvement of overall survival, which is a primary endpoint. This resulted in the phase III trial and FDA approval of this agent.

There have also been studies using sorafenib in combination with the induction chemotherapy, both from our group at MD Anderson and our German colleagues, which have shown that the addition of sorafenib to induction therapy does seem to improve event-free survival; this was seen in both FLT3-mutated as well as FLT3 wild-type disease. So there is now a new stream of thought that a lot of these FLT3 inhibitors—because they inhibit many pathways including FLT3, KIT, RAF, AXL, RAS, and VEGF—may actually have an impact, definitely in the FLT3 ITD-mutated AML, but also in FLT3 wild-type disease.

There are 3 new second-generation FLT3 inhibitors, which are just more modern, but they’re also more potent as single agents. These include 3 drugs: quizartinib, gilteritinib, and crenolanib. The first 2 are the ones that are advanced in clinical development in phase III studies, which were done this time with single-agent quizartinib and single-agent gilteritinib in relapsed/refractory acute myeloid leukemia. Furthermore, both of these studies have completed accrual.

The quizartinib phase III trial was a late-breaker at the EHA [European Hematology Association] meeting a couple of months ago in June, which showed that quizartinib, as single-agent therapy, did show an improvement in survival over standard therapies that the treating physicians gave. This was the primary endpoint, which has been met, so we expect quizartinib will be approved as a single agent in relapsed/refractory FLT3 ITD AML.

Gilteritinib also has a similar phase III trial in first-relapse FLT3 ITD and FLT3 D835 AML. The data have not yet been released, but we do know they have filed with the FDA, so we are expecting that both quizartinib and gilteritinib will become available probably by the end of 2018 or early 2019. This will give us many more options, in addition to sorafenib and midostaurin, for patients with FLT3-mutated AML.

Richard F. Schlenk, MD: There are 2 types of second-generation inhibitors, and gilteritinib and crenolanib are type 1. They inhibit the active and inactive FLT3 receptor kinase, whereas the type 2 inhibitor, quizartinib, only inhibits the inactive form of FLT3.

The second-generation inhibitors differ in half-life, which is quite important because, for example, quizartinib and gilteritinib have to be applied only once daily whereas crenolanib has to be applied 3 times daily. So you see there is a great difference in half-life, and there are some advantages for quizartinib and gilteritinib in that they have to be taken only once daily. However, if there are clinical problems—as we have already seen in acute myeloid leukemia patients—crenolanib may be preferable because it can be easily put off and the half-life is very short. The effect of the drug is very limited in time.

Resistance to second-generation FLT3 inhibitors can arise with new mutations. For example, patients have been identified with FLT3 internal tandem duplication, who have been treated with quizartinib. As a resistant mechanism, an FLT3 tyrosine kinase domain mutation came up; this is one mechanism to develop resistance to, for example, quizartinib. There are other mutations that can occur as point mutations in FLT3, but otherwise, AML is a clonal disease. Therefore, sometimes relapses or resistances to specific inhibitors come from other clones that are not related to FLT3. For example, sometimes we are able to inhibit the clone that is FLT3 mutation-positive, after which another clone arises, yielding a disease resistant to the FLT3 inhibitor.

Transcript Edited for Clarity 
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