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Midostaurin for FLT3-Mutant AML

Panelists: Naval G. Daver, MD, The University of Texas MD Anderson Cancer Center; Harry Erba, MD, PhD, Duke University; Mark J. Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center; Alexander Perl, MD, Abramson Cancer Center, University of Pennsylvania; Raajit K. Rampal, MD, PhD Memorial Sloan Kettering Cancer Center
Published: Wednesday, Feb 13, 2019



Transcript: 

Harry Erba, MD, PhD: So now let’s turn to the 3 FLT3 inhibitors—2 that are approved, and 1 that will hopefully or likely be approved next year. I’m going to start with what we’ve had since last year, April 2017, which is midostaurin. I’ll turn to Naval to give us an update there.

Naval G. Daver, MD: Sure. So it’s been very exciting, the FLT3 field. So midostaurin is the only approved FLT3 for frontline induction therapy at this time. This was based on the RATIFY study, a multicenter, multinational phase III study. As we commented, it took a long time because they had to screen 3500 patients to find the 700—20%, 25% incidence of FLT3. The study had midostaurin given on induction and consolidation, not with the chemotherapy. It was given day 8 through 21, with a 7 + 3 backbone, and the same was repeated there in consolidation day 8 through 21. And then there was a maintenance built in, where after you finished 3 or 4 consolidations, you’d get day 1 onward, continuous maintenance for a year with midostaurin or placebo, depending on what arm the patient was on, and the primary endpoint was survival.

So the study read out. It was presented by Dr Richard Stone at ASH [the American Society of Hematology Annual Meeting and Exposition] a couple of years ago, and it showed the survival endpoint of benefit had been met. And with an intent to treat, they did see that when you captured all responses over time, there was a significant improvement in the CR and CRI [complete remission and CR with incomplete recovery] rate. In the initial cutoff, it wasn’t met. But with the complete follow-up, there was an improvement.

So I think the study has shown benefit. Now, we weren’t jumping for joy. I mean, it’s not clinically solving the problem, but it was the first study, and it’s hard to believe…it was only 2, 3 years ago. It was the first study to show targeted therapy is going to push the bar in AML [acute myeloid leukemia]. Conceptually, I think that step is a big one, and now we hope we will improve further with some of the more targeted agents.

And I think the other thing that was very nice with the study update was the tolerability. So midostaurin was, in general, well tolerated. It has some adverse effects. A lot of patients have complained about this taste change or the way that the pill tastes, and there is some increase in skin rash, but not major, that led to discontinuation. And 1 important thing, for the community doctors especially, is that we have seen a few patients with other issues with this.

So, it’s rare. It’s 1%, or low, but because this is used more, I think people need to keep an eye out. If you see this, this may be an indication to start a steroid and call your local academic center, but, in general, it’s very well tolerated, with no major toxicity, and has led to the approval of the agent.

One point that Raajit mentioned that I think will be very important maybe for the next group of FLT3 inhibitors that are going to be approved in the salvage setting is that they did a subset. They did many, but 2, I thought, were really important in the community. One was the benefit was incrementally seen across all allele burdens. They did FLT3 low, they did FLT3 high, and TKD [tyrosine kinase domain]. They did not switch your FLT3-ITD [internal tandem duplication] high, which is a bad group, to a favorable group, and that’s too much to expect. But it gave you the same incremental benefits. So if you were poor, you did less poor; and if you were good, you did more good or better. So I think the point is that you use the midostaurin, and the transplant decision is something we’re all still trying to figure out. Do we transplant all of them or not? In our practice we have been.

And the second thing was they did an analysis of the time of relapse, and I was surprised to see this. Almost 40% to 50% of patients had lost their FLT3, and then we had done an analysis in the past that 10% to 15% could gain FLT3 who didn’t have it. So the point is, when you get to the gilteritinib and quizartinib, you need to check at that point in time. You cannot say, “A year ago, that was FLT3-positive. Let’s give him these drugs.”                     

Alexander Perl, MD: That’s 1 concern I have when we look at what the outcome of FLT3-mutated AML at relapse is. If they didn’t look then, you don’t know if that’s what they’re studying at all. And many of these studies looked at initial diagnoses, and then when they relapsed they assumed it was the same, but it may not be.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: So now let’s turn to the 3 FLT3 inhibitors—2 that are approved, and 1 that will hopefully or likely be approved next year. I’m going to start with what we’ve had since last year, April 2017, which is midostaurin. I’ll turn to Naval to give us an update there.

Naval G. Daver, MD: Sure. So it’s been very exciting, the FLT3 field. So midostaurin is the only approved FLT3 for frontline induction therapy at this time. This was based on the RATIFY study, a multicenter, multinational phase III study. As we commented, it took a long time because they had to screen 3500 patients to find the 700—20%, 25% incidence of FLT3. The study had midostaurin given on induction and consolidation, not with the chemotherapy. It was given day 8 through 21, with a 7 + 3 backbone, and the same was repeated there in consolidation day 8 through 21. And then there was a maintenance built in, where after you finished 3 or 4 consolidations, you’d get day 1 onward, continuous maintenance for a year with midostaurin or placebo, depending on what arm the patient was on, and the primary endpoint was survival.

So the study read out. It was presented by Dr Richard Stone at ASH [the American Society of Hematology Annual Meeting and Exposition] a couple of years ago, and it showed the survival endpoint of benefit had been met. And with an intent to treat, they did see that when you captured all responses over time, there was a significant improvement in the CR and CRI [complete remission and CR with incomplete recovery] rate. In the initial cutoff, it wasn’t met. But with the complete follow-up, there was an improvement.

So I think the study has shown benefit. Now, we weren’t jumping for joy. I mean, it’s not clinically solving the problem, but it was the first study, and it’s hard to believe…it was only 2, 3 years ago. It was the first study to show targeted therapy is going to push the bar in AML [acute myeloid leukemia]. Conceptually, I think that step is a big one, and now we hope we will improve further with some of the more targeted agents.

And I think the other thing that was very nice with the study update was the tolerability. So midostaurin was, in general, well tolerated. It has some adverse effects. A lot of patients have complained about this taste change or the way that the pill tastes, and there is some increase in skin rash, but not major, that led to discontinuation. And 1 important thing, for the community doctors especially, is that we have seen a few patients with other issues with this.

So, it’s rare. It’s 1%, or low, but because this is used more, I think people need to keep an eye out. If you see this, this may be an indication to start a steroid and call your local academic center, but, in general, it’s very well tolerated, with no major toxicity, and has led to the approval of the agent.

One point that Raajit mentioned that I think will be very important maybe for the next group of FLT3 inhibitors that are going to be approved in the salvage setting is that they did a subset. They did many, but 2, I thought, were really important in the community. One was the benefit was incrementally seen across all allele burdens. They did FLT3 low, they did FLT3 high, and TKD [tyrosine kinase domain]. They did not switch your FLT3-ITD [internal tandem duplication] high, which is a bad group, to a favorable group, and that’s too much to expect. But it gave you the same incremental benefits. So if you were poor, you did less poor; and if you were good, you did more good or better. So I think the point is that you use the midostaurin, and the transplant decision is something we’re all still trying to figure out. Do we transplant all of them or not? In our practice we have been.

And the second thing was they did an analysis of the time of relapse, and I was surprised to see this. Almost 40% to 50% of patients had lost their FLT3, and then we had done an analysis in the past that 10% to 15% could gain FLT3 who didn’t have it. So the point is, when you get to the gilteritinib and quizartinib, you need to check at that point in time. You cannot say, “A year ago, that was FLT3-positive. Let’s give him these drugs.”                     

Alexander Perl, MD: That’s 1 concern I have when we look at what the outcome of FLT3-mutated AML at relapse is. If they didn’t look then, you don’t know if that’s what they’re studying at all. And many of these studies looked at initial diagnoses, and then when they relapsed they assumed it was the same, but it may not be.

Transcript Edited for Clarity
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