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Role of FLT3 Inhibitors for Treating Relapsed AML

Insights From: Naval G. Daver, MD, MD Anderson Cancer Center; Anthony Mato, MD, MSCE, Memorial Sloan Kettering Center
Published: Monday, Jun 24, 2019



Transcript:

Naval G. Daver, MD:
The FLT3 mutation historically has been associated with an inferior outcome in acute myeloid leukemia [AML]. This was based on studies done about 15 years ago where we looked at thousands of patients who had different mutations and found that the ones who had a FLT3 had a very poor survival, 5-year survival was 20%. This led to a lot of efforts to improve outcomes, including the use of transplant, which showed some improvement from 20% to 35% or so in survival, as well as development of a number of FLT3 inhibitors. And we’ve gone through 4 or 5 different types of FLT3 inhibitors, and the first one that finally made it to approval was a drug called midostaurin. This was used in the frontline setting, a phase III combined with induction chemotherapy and showed that you could improve both overall response rate and survival significantly by adding midostaurin to induction, versus doing induction alone in FLT3-mutated AML.

This was a major breakthrough. In fact, in the patients who got midostaurin in the FLT3-mutated situation, and were able to go to transplant in the frontline setting, we had a 5-year survival of 65%, which is amazing considering that it was 20% just 15 years ago when we identified this as a high-risk feature. So we’re doing better, but in the end you really do see that at about 5 years about 40% to 50% of these patients will relapse with their disease. So we still need a lot of treatments in the relapsed setting.

Historically we would do chemotherapy again with higher doses and broader combinations like FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin], MEK inhibitor, or maybe hypomethylating agent if it was an older patient. And we would get somewhere between 15%, 20% response rates, often with a lot of toxicities, and the only real chance of curing these patients would be to go to transplant, but very few of them would make it because of toxicities, because of age, because the chemotherapy would further destroy their overall performance status.

So this has led to 2 very powerful FLT3 inhibitors that have been developed and salvaged. One of them is gilteritinib, the other is quizartinib. Quizartinib is actually the first one to be developed in the relapsed/refractory setting and the study called a QuANTUM-R, which was a phase III randomized study of 400 patients. Randomized patients received single-agent oral quizartinib at a lower dose, 30 mg to 60 mg, versus investigator choice chemotherapy, which was usually high-dose chemotherapy, 3 or 4 drug combination, IV [intravenous], inpatient, or hypomethylating agent.

The primary endpoint was overall survival. And the study, which was presented almost exactly a year ago at the EHA [European Hematology Association] meeting in 2018 by Dr Jorge Cortes ,MD, showed quite striking results. The overall survival endpoint was met, which was very positive. But more importantly, when you look at the response rates, in the chemotherapy arm, or the hypomethylating arm versus the quizartinib arm, you see that the response rates are almost doubled with quizartinib. So the CR/CRi [complete response/complete response with incomplete hematologic recovery] rate is about 50% with a single oral very well tolerated agent versus only 25% with our best very potent, very toxic chemotherapy regimens.

So to me the study showed 2 things. One is that the FLT3 inhibitors are very potent, and as single agents actually can get a lot of patients to transplant, about 35% went to transplant with quizartinib. But 2, really it shows how ineffective chemotherapy is in this situation. I think a lot of us overestimated the ability of the chemotherapy, and this study showed that with chemotherapy only 10% made it to transplant. The 1-year survival was less than 15%. So you’re almost doing palliative treatment, which has a lot of toxicities.

I think this kind of set the stage to use FLT3 inhibitors in that setting. The quizartinib is still under review with the FDA at this time, and hopefully will eventually get an approval. There’s also a frontline study combining it with chemotherapy. The other drug, gilteritinib, actually does have an FDA approval, very recent. The study was almost exactly the same design as the quizartinib relapse study. It took patients who had relapsed FLT3-mutated AML and gave them gilteritinib versus investigator choice.

One of the advantages of gilteritinib is that it does hit both the ITD, which is a common mutation, and the D835. And so we think that another 10%, 15% of patients who maybe could not get quizartinib could get the gilteritinib. This study again met its primary endpoint, showed a very impressive overall survival of 10 months versus 6-and-a-half months that was achieved on the chemotherapy arm. And especially for people going to transplant, there was about a 25%, 30% chance of being alive at 2 years to 3 years, which would have never been heard of in the past in a FLT3-mutated relapsed patient. So based on this, gilteritinib is FDA approved.

We really think that these 2 studies are very different. One of the major differences is that the quizartinib study focused on people who had relapsed within 6 months or were refractory, which is a relatively high-risk population. Whereas the gilteritinib study allowed all relapses. The majority of them were 6 months or earlier, but there were some late relapses who could do differently, and the gilteritinib study covered D835, whereas the quizartinib didn’t.

In the end, just like in CML [chronic myeloid leukemia] where we have 5 TKIs [tyrosine kinase inhibitors], and we end up using all of them because patients fail one or they don’t tolerate one, they cannot afford one. I think the key is that we need to have multiple potent FLT3 inhibitors available so that we can sequence these, because none of them is curing the patient. So the more options we have, the better the survival will be.


Transcript Edited for Clarity
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Transcript:

Naval G. Daver, MD:
The FLT3 mutation historically has been associated with an inferior outcome in acute myeloid leukemia [AML]. This was based on studies done about 15 years ago where we looked at thousands of patients who had different mutations and found that the ones who had a FLT3 had a very poor survival, 5-year survival was 20%. This led to a lot of efforts to improve outcomes, including the use of transplant, which showed some improvement from 20% to 35% or so in survival, as well as development of a number of FLT3 inhibitors. And we’ve gone through 4 or 5 different types of FLT3 inhibitors, and the first one that finally made it to approval was a drug called midostaurin. This was used in the frontline setting, a phase III combined with induction chemotherapy and showed that you could improve both overall response rate and survival significantly by adding midostaurin to induction, versus doing induction alone in FLT3-mutated AML.

This was a major breakthrough. In fact, in the patients who got midostaurin in the FLT3-mutated situation, and were able to go to transplant in the frontline setting, we had a 5-year survival of 65%, which is amazing considering that it was 20% just 15 years ago when we identified this as a high-risk feature. So we’re doing better, but in the end you really do see that at about 5 years about 40% to 50% of these patients will relapse with their disease. So we still need a lot of treatments in the relapsed setting.

Historically we would do chemotherapy again with higher doses and broader combinations like FLAG-IDA [fludarabine/cytarabine/G-CSF/idarubicin], MEK inhibitor, or maybe hypomethylating agent if it was an older patient. And we would get somewhere between 15%, 20% response rates, often with a lot of toxicities, and the only real chance of curing these patients would be to go to transplant, but very few of them would make it because of toxicities, because of age, because the chemotherapy would further destroy their overall performance status.

So this has led to 2 very powerful FLT3 inhibitors that have been developed and salvaged. One of them is gilteritinib, the other is quizartinib. Quizartinib is actually the first one to be developed in the relapsed/refractory setting and the study called a QuANTUM-R, which was a phase III randomized study of 400 patients. Randomized patients received single-agent oral quizartinib at a lower dose, 30 mg to 60 mg, versus investigator choice chemotherapy, which was usually high-dose chemotherapy, 3 or 4 drug combination, IV [intravenous], inpatient, or hypomethylating agent.

The primary endpoint was overall survival. And the study, which was presented almost exactly a year ago at the EHA [European Hematology Association] meeting in 2018 by Dr Jorge Cortes ,MD, showed quite striking results. The overall survival endpoint was met, which was very positive. But more importantly, when you look at the response rates, in the chemotherapy arm, or the hypomethylating arm versus the quizartinib arm, you see that the response rates are almost doubled with quizartinib. So the CR/CRi [complete response/complete response with incomplete hematologic recovery] rate is about 50% with a single oral very well tolerated agent versus only 25% with our best very potent, very toxic chemotherapy regimens.

So to me the study showed 2 things. One is that the FLT3 inhibitors are very potent, and as single agents actually can get a lot of patients to transplant, about 35% went to transplant with quizartinib. But 2, really it shows how ineffective chemotherapy is in this situation. I think a lot of us overestimated the ability of the chemotherapy, and this study showed that with chemotherapy only 10% made it to transplant. The 1-year survival was less than 15%. So you’re almost doing palliative treatment, which has a lot of toxicities.

I think this kind of set the stage to use FLT3 inhibitors in that setting. The quizartinib is still under review with the FDA at this time, and hopefully will eventually get an approval. There’s also a frontline study combining it with chemotherapy. The other drug, gilteritinib, actually does have an FDA approval, very recent. The study was almost exactly the same design as the quizartinib relapse study. It took patients who had relapsed FLT3-mutated AML and gave them gilteritinib versus investigator choice.

One of the advantages of gilteritinib is that it does hit both the ITD, which is a common mutation, and the D835. And so we think that another 10%, 15% of patients who maybe could not get quizartinib could get the gilteritinib. This study again met its primary endpoint, showed a very impressive overall survival of 10 months versus 6-and-a-half months that was achieved on the chemotherapy arm. And especially for people going to transplant, there was about a 25%, 30% chance of being alive at 2 years to 3 years, which would have never been heard of in the past in a FLT3-mutated relapsed patient. So based on this, gilteritinib is FDA approved.

We really think that these 2 studies are very different. One of the major differences is that the quizartinib study focused on people who had relapsed within 6 months or were refractory, which is a relatively high-risk population. Whereas the gilteritinib study allowed all relapses. The majority of them were 6 months or earlier, but there were some late relapses who could do differently, and the gilteritinib study covered D835, whereas the quizartinib didn’t.

In the end, just like in CML [chronic myeloid leukemia] where we have 5 TKIs [tyrosine kinase inhibitors], and we end up using all of them because patients fail one or they don’t tolerate one, they cannot afford one. I think the key is that we need to have multiple potent FLT3 inhibitors available so that we can sequence these, because none of them is curing the patient. So the more options we have, the better the survival will be.


Transcript Edited for Clarity
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