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Implications of the RATIFY Trial in Acute Myeloid Leukemia

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: Midostaurin is an example of a first-generation type 1 FLT3 inhibitor. The first-generation FLT3 inhibitors are generally less specific for FLT3 and have multiple targets. In fact, midostaurin is not only a tyrosine kinase inhibitor [TKI] but also inhibits a number of serine/threonine protein kinases. It is a type 1 inhibitor, meaning that it binds to the ATP [adenosine triphosphate] binding site and will inhibit wild-type FLT3 but also FLT3 with an ITD [internal tandem duplication] mutation or a tyrosine kinase domain [TKD] mutation.
The RATIFY trial was an international phase III study evaluating the benefit of midostaurin versus a placebo in addition to induction chemotherapy with standard high-dose cytarabine consolidation, followed by maintenance for 1 year with either midostaurin or placebo. Over 700 patients were treated in the study with the primary endpoint being overall survival. The majority of patients treated with midostaurin experienced superior results to those that received placebo. The median survivals were dramatically different—75 months with midostaurin versus about 25 months with placebo—but this dramatic difference was really due to the fact that the survival curves by Kaplan-Meier analysis plateaued around 50%. If you look at the 4-year survival, there was a 23% reduction in the risk of death. The survival of 4 years with midostaurin was 54%, and it was 47% with placebo.

This is the first time that the addition of any agent to standard chemotherapy in the past 40 years has resulted in a benefit in terms of survival for patients with AML, which is most dramatic because this is a group of patients who often have a very poor survival rate, especially those with FLT3 internal tandem duplication.

What isn’t clear from the results of the midostaurin or RATIFY trial is how this benefit was achieved in patients with an FLT3 mutation. Of course, they all had to have an ITD or TKD mutation; however, we know that the median number of mutations in an AML sample is about 4, so other mutations may be present. We don’t have the analysis of the majority of those other mutations. There was a presentation looking at the interaction with nucleophosmin and an FLT3 mutation in this study, again showing that patients with mutated nucleophosmin, especially with an FLT3 TKD mutation, do very well.

One thing that has led us to question whether the benefit of midostaurin was truly due to inhibition of FLT3 or some of the other targets that are inhibited by midostaurin is the fact that when we look at the hazard ratio for survival in subsets of patients based on high allelic burden or low allelic burden, with FLT3 ITD or even the FLT3 TKD, there was a benefit in all groups. In fact, the most dramatic benefit was in patients with an FLT3 TKD mutation, leaving some to wonder if the benefit of midostaurin may be due to not only inhibition of FLT3 but some of these other targets that might be important in the pathogenesis of AML. Whether we need a specific inhibitor for ITD or not is unclear, and it really has to do with the best FLT3 inhibitor, which will be judged by activity in the patient population toxicity profiles and such.

Naval G. Daver, MD: The other important thing that was seen with the RATIFY study is that midostaurin was not used continuously, but rather between days 8 through 21. This is important to note because there were phase II studies where midostaurin was used from day 1 through 28, the entire cycle, during which there was a lot of GI [gastrointestinal] toxicity. So, to avoid the overlapping chemotherapy and midostaurin, midostaurin was started on day 8, which was right after the completion of the 3+7, which goes on for 7 days.

What we are now seeing is that most community physicians are able to get the results of their FLT3 testing in 6 or 7 days, and they are able to add the midostaurin on day 8 or 9. But what we would recommend at MD Anderson and most other centers is, even if it takes you a bit longer to get the testing results, it’s more important to add the midostaurin rather than worry about day 8. I get a lot of calls from physicians who say, “I got the results on day 10 or 11, what should I do?” And I recommend to still do the 14 days of midostaurin. Instead of doing 8 to 21, you could do day 11 through 25, and so on and so forth. As of now, I would not avoid using the midostaurin because it yields the greatest benefit.


Transcipt Edited for Clarity
 
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Transcript: 

Harry Erba, MD, PhD: Midostaurin is an example of a first-generation type 1 FLT3 inhibitor. The first-generation FLT3 inhibitors are generally less specific for FLT3 and have multiple targets. In fact, midostaurin is not only a tyrosine kinase inhibitor [TKI] but also inhibits a number of serine/threonine protein kinases. It is a type 1 inhibitor, meaning that it binds to the ATP [adenosine triphosphate] binding site and will inhibit wild-type FLT3 but also FLT3 with an ITD [internal tandem duplication] mutation or a tyrosine kinase domain [TKD] mutation.
The RATIFY trial was an international phase III study evaluating the benefit of midostaurin versus a placebo in addition to induction chemotherapy with standard high-dose cytarabine consolidation, followed by maintenance for 1 year with either midostaurin or placebo. Over 700 patients were treated in the study with the primary endpoint being overall survival. The majority of patients treated with midostaurin experienced superior results to those that received placebo. The median survivals were dramatically different—75 months with midostaurin versus about 25 months with placebo—but this dramatic difference was really due to the fact that the survival curves by Kaplan-Meier analysis plateaued around 50%. If you look at the 4-year survival, there was a 23% reduction in the risk of death. The survival of 4 years with midostaurin was 54%, and it was 47% with placebo.

This is the first time that the addition of any agent to standard chemotherapy in the past 40 years has resulted in a benefit in terms of survival for patients with AML, which is most dramatic because this is a group of patients who often have a very poor survival rate, especially those with FLT3 internal tandem duplication.

What isn’t clear from the results of the midostaurin or RATIFY trial is how this benefit was achieved in patients with an FLT3 mutation. Of course, they all had to have an ITD or TKD mutation; however, we know that the median number of mutations in an AML sample is about 4, so other mutations may be present. We don’t have the analysis of the majority of those other mutations. There was a presentation looking at the interaction with nucleophosmin and an FLT3 mutation in this study, again showing that patients with mutated nucleophosmin, especially with an FLT3 TKD mutation, do very well.

One thing that has led us to question whether the benefit of midostaurin was truly due to inhibition of FLT3 or some of the other targets that are inhibited by midostaurin is the fact that when we look at the hazard ratio for survival in subsets of patients based on high allelic burden or low allelic burden, with FLT3 ITD or even the FLT3 TKD, there was a benefit in all groups. In fact, the most dramatic benefit was in patients with an FLT3 TKD mutation, leaving some to wonder if the benefit of midostaurin may be due to not only inhibition of FLT3 but some of these other targets that might be important in the pathogenesis of AML. Whether we need a specific inhibitor for ITD or not is unclear, and it really has to do with the best FLT3 inhibitor, which will be judged by activity in the patient population toxicity profiles and such.

Naval G. Daver, MD: The other important thing that was seen with the RATIFY study is that midostaurin was not used continuously, but rather between days 8 through 21. This is important to note because there were phase II studies where midostaurin was used from day 1 through 28, the entire cycle, during which there was a lot of GI [gastrointestinal] toxicity. So, to avoid the overlapping chemotherapy and midostaurin, midostaurin was started on day 8, which was right after the completion of the 3+7, which goes on for 7 days.

What we are now seeing is that most community physicians are able to get the results of their FLT3 testing in 6 or 7 days, and they are able to add the midostaurin on day 8 or 9. But what we would recommend at MD Anderson and most other centers is, even if it takes you a bit longer to get the testing results, it’s more important to add the midostaurin rather than worry about day 8. I get a lot of calls from physicians who say, “I got the results on day 10 or 11, what should I do?” And I recommend to still do the 14 days of midostaurin. Instead of doing 8 to 21, you could do day 11 through 25, and so on and so forth. As of now, I would not avoid using the midostaurin because it yields the greatest benefit.


Transcipt Edited for Clarity
 
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Rapid Reviews in Oncology®: Practice-Changing Data in Acute Myeloid Leukemia: A Rapid Update From Atlanta OnlineDec 21, 20182.0
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