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Quizartinib's Potential Role in Treating AML

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: Friday, Oct 12, 2018



Transcript:

Harry Erba, MD, PhD: I have not yet used quizartinib in patients with acute myeloid leukemia, but if it does get approved in the patients with FLT3 ITD [internal tandem duplication]-mutated AML in the relapsed/refractory setting, I think it provides an excellent possibility for therapy as a bridge to allogeneic stem cell transplantation. I say that because the drug seems to have a favorable toxicity profile and does not require inpatient hospitalization. The response rates were higher than what we saw with chemotherapy, the duration of which were longer than chemotherapy, and this translated into more patients having received crizotinib bridging to allogeneic transplant, which is the only potentially curative option. Now, one thing that we would consider for a patient who undergoes allogeneic stem cell transplant for FLT3 ITD-mutated AML and who has already responded to a drug like quizartinib is using quizartinib as a maintenance. We don’t have any data to support that yet, but I would surely consider that as an option given the high relapse rate in FLT3 ITD-mutated patients, even after allogeneic stem cell transplant.

The question for all of us will be, if the drug is available in relapsed/refractory patients, will there be a temptation to consider the use of a more potent and more specific second-generation drug, such as quizartinib, in addition to initial chemotherapy and consolidation? Now, of course, we want to wait for the results of the QuANTUM-First study to see if there’s a benefit in terms of event-free survival, the primary endpoint in that study. On the other hand, if the drug is available and we do have safety data about the combination, I wouldn’t be surprised if some of us would choose to use such an inhibitor as quizartinib in place of midostaurin. The caveat there is it then supposes that the benefit we saw from midostaurin was only due to inhibition of FLT3 ITD and TKD [tyrosine kinase domain] mutations. If that’s not true and other enzymes are being inhibited, then there may not be a benefit or the same degree of benefit with quizartinib. And so, there’s much opinion around this point.

Richard F. Schlenk, MD: We can use quizartinib in clinical practice if it’s available. I think it will be approved first for patients with relapsed and refractory AML. It will be used as if it’s approved as a single agent. However, I think there are several trials now looking also into the relapsed and refractory setting and whether quizartinib can be combined with intensive chemotherapy to improve the results for the single-agent quizartinib patient population. I think it will be either used as single agent or in combination with a standard, let’s say salvage therapy, in this patient population.

Naval G. Daver, MD: We now have a number of new quizartinib combination studies, which I’m really excited about. We have a frontline study in older patients with AML who are not candidates for induction where we’re combining a decitabine 10-day regimen, which is considered low intensity, with quizartinib. We also have a study of novel-novel combinations where we’re combining quizartinib with another exciting drug in AML called venetoclax. Additionally, we’re combining quizartinib with an MDM2 inhibitor.

We think that these combinations are going to be very important because we have seen that although the response rates with FLT3 inhibitors are very good—45% to 50%—the duration of response is quite short, usually in the range of 14 to 18 weeks. If you cannot get these patients quickly to a stem cell transplant, you really are not getting a very durable activity. So we believe that by adding hypomethylating agents, chemotherapy, or rationally designed combinations such as venetoclax with FLT3 inhibitors—for which there are a lot of data published from our site and from AbbVie—or MDM2 inhibitors with quizartinib, maybe we can increase this duration of response to 6, 9, or 12 months so that more patients have extended benefit and a longer response, allowing them to go to stem cell transplant.


Transcript Edited for Clarity
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Transcript:

Harry Erba, MD, PhD: I have not yet used quizartinib in patients with acute myeloid leukemia, but if it does get approved in the patients with FLT3 ITD [internal tandem duplication]-mutated AML in the relapsed/refractory setting, I think it provides an excellent possibility for therapy as a bridge to allogeneic stem cell transplantation. I say that because the drug seems to have a favorable toxicity profile and does not require inpatient hospitalization. The response rates were higher than what we saw with chemotherapy, the duration of which were longer than chemotherapy, and this translated into more patients having received crizotinib bridging to allogeneic transplant, which is the only potentially curative option. Now, one thing that we would consider for a patient who undergoes allogeneic stem cell transplant for FLT3 ITD-mutated AML and who has already responded to a drug like quizartinib is using quizartinib as a maintenance. We don’t have any data to support that yet, but I would surely consider that as an option given the high relapse rate in FLT3 ITD-mutated patients, even after allogeneic stem cell transplant.

The question for all of us will be, if the drug is available in relapsed/refractory patients, will there be a temptation to consider the use of a more potent and more specific second-generation drug, such as quizartinib, in addition to initial chemotherapy and consolidation? Now, of course, we want to wait for the results of the QuANTUM-First study to see if there’s a benefit in terms of event-free survival, the primary endpoint in that study. On the other hand, if the drug is available and we do have safety data about the combination, I wouldn’t be surprised if some of us would choose to use such an inhibitor as quizartinib in place of midostaurin. The caveat there is it then supposes that the benefit we saw from midostaurin was only due to inhibition of FLT3 ITD and TKD [tyrosine kinase domain] mutations. If that’s not true and other enzymes are being inhibited, then there may not be a benefit or the same degree of benefit with quizartinib. And so, there’s much opinion around this point.

Richard F. Schlenk, MD: We can use quizartinib in clinical practice if it’s available. I think it will be approved first for patients with relapsed and refractory AML. It will be used as if it’s approved as a single agent. However, I think there are several trials now looking also into the relapsed and refractory setting and whether quizartinib can be combined with intensive chemotherapy to improve the results for the single-agent quizartinib patient population. I think it will be either used as single agent or in combination with a standard, let’s say salvage therapy, in this patient population.

Naval G. Daver, MD: We now have a number of new quizartinib combination studies, which I’m really excited about. We have a frontline study in older patients with AML who are not candidates for induction where we’re combining a decitabine 10-day regimen, which is considered low intensity, with quizartinib. We also have a study of novel-novel combinations where we’re combining quizartinib with another exciting drug in AML called venetoclax. Additionally, we’re combining quizartinib with an MDM2 inhibitor.

We think that these combinations are going to be very important because we have seen that although the response rates with FLT3 inhibitors are very good—45% to 50%—the duration of response is quite short, usually in the range of 14 to 18 weeks. If you cannot get these patients quickly to a stem cell transplant, you really are not getting a very durable activity. So we believe that by adding hypomethylating agents, chemotherapy, or rationally designed combinations such as venetoclax with FLT3 inhibitors—for which there are a lot of data published from our site and from AbbVie—or MDM2 inhibitors with quizartinib, maybe we can increase this duration of response to 6, 9, or 12 months so that more patients have extended benefit and a longer response, allowing them to go to stem cell transplant.


Transcript Edited for Clarity
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