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RATIFY Trial: Midostaurin's Role in Treating AML

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, Perelman School of Medicine; Eunice Wang, MD, Roswell Park Cancer Institute
Published: Friday, Feb 09, 2018



Transcript: 

Harry Erba, MD, PhD: Let’s move on now to the 2 treatments that have been developed to target some of these mutations that we have found. And the group of drugs that have been intensely studied over the last 10 years or so is the FLT3 inhibitors. One is now approved for treatment of adults with FLT3-mutated AML, and that’s midostaurin. Eunice, do you want to bring us through the data for that?

Eunice Wang, MD: We were actually one of the sites for the RATIFY trial, which was conducted over 10 years ago, initially. This trial was looking at a drug, midostaurin. Now this drug is, I have to say, not the newest agent on the block. At the time, it was an agent that was developed as a pan-tyrosine kinase inhibitor. It inhibited multiple other tyrosine kinases, but also hit FLT3. The hypothesis was that we knew from earlier studies done in AML populations that one-third or a quarter of patients with AML—newly diagnosed, particularly younger patients—when you looked at their molecular profiling and we looked for the presence of the FLT3 mutation, that those patients had, almost up to a third of them, either a FLT3 tyrosine kinase or a FLT3-ITG mutation.

And at least for the ITG mutation, which is slightly more common, the prognosis for those patients was worse. Now there are conflicting data, but the older data suggested that those patients who had FLT3-ITG-mutant AML tended to present with higher white blood cell counts, hyperleukocytosis, and more aggressive proliferative disease. They were able to achieve similar rates of complete remission as patients who were FLT3 wild-type. However, they had a very short event-free survival, and they tended to have high rates of recurrence and a shorter overall outcome. So, their prognosis was significantly worse.
Midostaurin was developed or thought of, even though it’s a pan-tyrosine kinase inhibitor, as potentially an agent that could target FLT3 and both TKG- and ITG-mutated cells in vitro. And so, you could add it to standard 7-and-3 chemotherapy for these younger patients because they had the same CR rates, but could you get better effects by adding a targeted FLT3 agent to standard chemotherapy?

Earlier studies that were done in the phase I, II setting up in Boston had demonstrated that maybe you can get higher CR rates. So, this study was then actually done through the cooperative group. It was a very, very large study where they screened over 3,000 patients with the presence of the FLT3 mutation and were able to identify 700 patients. Those patients were randomized to receive either midostaurin plus standard 7-and-3 chemotherapy or placebo 7-and-3 chemotherapy, and then they were followed for overall outcomes.

Now, this study utilized midostaurin starting for a 2-week period during induction chemotherapy. Then, patients receive additional shorter periods of treatment with a FLT3 inhibitor with high-dose cytarabine. If they then were able to go on to transplant, they were allowed to go to transplant. So, up to two-thirds of patients eventually received an allogeneic transplant either in first remission or in the subsequent salvage setting. And if you were not able to go on to further chemotherapy or further transplant, you could get consolidation maintenance. So, there’s a lot of FLT3 use there. But the primary endpoints were really to look at the overall outcome efficacy, event-free survival, etc.

When this study was presented at ASH just a couple of years ago, the data were actually very startling because for years—and Jorge can tell you better than I can—we’ve added things to 7-and-3 chemotherapy. We’ve added this drug and that drug to 7-and-3 chemotherapy. When we get to the randomized trial and we look at the experimental versus the control arm, it ends up being a wash. How many ASH meetings have you gone to where we’ve come in with great excitement about a phase II study, and we get to the phase III setting and it’s negative, right?

I think that this study actually took many, many years to read out, mostly because a lot of the patients went to transplant, so the endpoints were low, or it took a long time to accumulate. But this is the first agent to actually, when added to chemotherapy, really show a benefit. And that was a benefit seen as a 4-year overall survival benefit. Survival curves were distinct, and they remain distinct. In fact, when you look carefully at the curves, the difference in the overall survival curve seems to separate out shortly after induction and continue along the therapy during induction and consolidation.

Now, interpreting the data, there is no difference in CR. But there is a difference right after that time point. There was no minimal residual disease testing that was done. There also was, when patients went off to transplant and the other patients stayed on, the ability for those patients who didn’t go on to transplant from first remission to receive maintenance therapy for up to 12 months of midostaurin. But there was no ability in the original study design to look at the significance of the 12-month maintenance period. Midostaurin was actually the first drug to be approved for the treatment of newly diagnosed patients with FLT3-mutant AML in conjunction with standard chemotherapy for induction in consolidation only. What are your experiences with midostaurin? You don’t use midostaurin. Do you use midostaurin?

Jorge E. Cortes, MD: We haven’t. What happened with midostaurin is that we almost forgot about it, because the study with FLT3 took so long.

Eunice Wang, MD: There was some toxicity with it.

Jorge E. Cortes, MD: Yes. Back in the beginning, when we were doing it as a single agent where we participated on those trials, there was a little bit of GI toxicity. But in general, when you add it to the chemotherapy, it really doesn’t add much to the toxicity.

Eunice Wang, MD: They’re already getting intensive chemo, right?

Jorge E. Cortes, MD: Exactly. From the safety point of view, my perception—and, of course, what was confirmed with the RATIFY trial—is that it really is a pretty safe combination to give; that you get what you get with the chemotherapy, but that’s about it.
I think it is an important addition, because we’ve always felt that by adding something—a FLT3 inhibitor—to chemotherapy, you would get a benefit. We’ve done some single-arm studies and looked at historical controls, including the complications of those comparisons and how you analyze the data, but that was always our belief or our hope. And the RATIFY trial ratifies that.

Eunice Wang, MD: I think it’s the first trial to show a positive benefit for this type of targeted agent, a tyrosine kinase inhibitor. I think ever since BCR-ABL inhibitors got developed for CML, there’s always been this belief of, could we develop a kinase inhibitor for acute leukemias?

Jorge E. Cortes, MD: And it’s actually fair to say that part of the reason why it takes so long is because the events were not happening as fast as they could.

Eunice Wang, MD: Right.

Alexander E. Perl, MD: Which is a good thing, and this is a high-risk population.

Jorge E. Cortes, MD: It’s a good thing. So, you know it took very long, but it was a good thing, because now we have this population of high-risk patients—and all of a sudden, we’re not having the rate of events that we thought we would be having.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: Let’s move on now to the 2 treatments that have been developed to target some of these mutations that we have found. And the group of drugs that have been intensely studied over the last 10 years or so is the FLT3 inhibitors. One is now approved for treatment of adults with FLT3-mutated AML, and that’s midostaurin. Eunice, do you want to bring us through the data for that?

Eunice Wang, MD: We were actually one of the sites for the RATIFY trial, which was conducted over 10 years ago, initially. This trial was looking at a drug, midostaurin. Now this drug is, I have to say, not the newest agent on the block. At the time, it was an agent that was developed as a pan-tyrosine kinase inhibitor. It inhibited multiple other tyrosine kinases, but also hit FLT3. The hypothesis was that we knew from earlier studies done in AML populations that one-third or a quarter of patients with AML—newly diagnosed, particularly younger patients—when you looked at their molecular profiling and we looked for the presence of the FLT3 mutation, that those patients had, almost up to a third of them, either a FLT3 tyrosine kinase or a FLT3-ITG mutation.

And at least for the ITG mutation, which is slightly more common, the prognosis for those patients was worse. Now there are conflicting data, but the older data suggested that those patients who had FLT3-ITG-mutant AML tended to present with higher white blood cell counts, hyperleukocytosis, and more aggressive proliferative disease. They were able to achieve similar rates of complete remission as patients who were FLT3 wild-type. However, they had a very short event-free survival, and they tended to have high rates of recurrence and a shorter overall outcome. So, their prognosis was significantly worse.
Midostaurin was developed or thought of, even though it’s a pan-tyrosine kinase inhibitor, as potentially an agent that could target FLT3 and both TKG- and ITG-mutated cells in vitro. And so, you could add it to standard 7-and-3 chemotherapy for these younger patients because they had the same CR rates, but could you get better effects by adding a targeted FLT3 agent to standard chemotherapy?

Earlier studies that were done in the phase I, II setting up in Boston had demonstrated that maybe you can get higher CR rates. So, this study was then actually done through the cooperative group. It was a very, very large study where they screened over 3,000 patients with the presence of the FLT3 mutation and were able to identify 700 patients. Those patients were randomized to receive either midostaurin plus standard 7-and-3 chemotherapy or placebo 7-and-3 chemotherapy, and then they were followed for overall outcomes.

Now, this study utilized midostaurin starting for a 2-week period during induction chemotherapy. Then, patients receive additional shorter periods of treatment with a FLT3 inhibitor with high-dose cytarabine. If they then were able to go on to transplant, they were allowed to go to transplant. So, up to two-thirds of patients eventually received an allogeneic transplant either in first remission or in the subsequent salvage setting. And if you were not able to go on to further chemotherapy or further transplant, you could get consolidation maintenance. So, there’s a lot of FLT3 use there. But the primary endpoints were really to look at the overall outcome efficacy, event-free survival, etc.

When this study was presented at ASH just a couple of years ago, the data were actually very startling because for years—and Jorge can tell you better than I can—we’ve added things to 7-and-3 chemotherapy. We’ve added this drug and that drug to 7-and-3 chemotherapy. When we get to the randomized trial and we look at the experimental versus the control arm, it ends up being a wash. How many ASH meetings have you gone to where we’ve come in with great excitement about a phase II study, and we get to the phase III setting and it’s negative, right?

I think that this study actually took many, many years to read out, mostly because a lot of the patients went to transplant, so the endpoints were low, or it took a long time to accumulate. But this is the first agent to actually, when added to chemotherapy, really show a benefit. And that was a benefit seen as a 4-year overall survival benefit. Survival curves were distinct, and they remain distinct. In fact, when you look carefully at the curves, the difference in the overall survival curve seems to separate out shortly after induction and continue along the therapy during induction and consolidation.

Now, interpreting the data, there is no difference in CR. But there is a difference right after that time point. There was no minimal residual disease testing that was done. There also was, when patients went off to transplant and the other patients stayed on, the ability for those patients who didn’t go on to transplant from first remission to receive maintenance therapy for up to 12 months of midostaurin. But there was no ability in the original study design to look at the significance of the 12-month maintenance period. Midostaurin was actually the first drug to be approved for the treatment of newly diagnosed patients with FLT3-mutant AML in conjunction with standard chemotherapy for induction in consolidation only. What are your experiences with midostaurin? You don’t use midostaurin. Do you use midostaurin?

Jorge E. Cortes, MD: We haven’t. What happened with midostaurin is that we almost forgot about it, because the study with FLT3 took so long.

Eunice Wang, MD: There was some toxicity with it.

Jorge E. Cortes, MD: Yes. Back in the beginning, when we were doing it as a single agent where we participated on those trials, there was a little bit of GI toxicity. But in general, when you add it to the chemotherapy, it really doesn’t add much to the toxicity.

Eunice Wang, MD: They’re already getting intensive chemo, right?

Jorge E. Cortes, MD: Exactly. From the safety point of view, my perception—and, of course, what was confirmed with the RATIFY trial—is that it really is a pretty safe combination to give; that you get what you get with the chemotherapy, but that’s about it.
I think it is an important addition, because we’ve always felt that by adding something—a FLT3 inhibitor—to chemotherapy, you would get a benefit. We’ve done some single-arm studies and looked at historical controls, including the complications of those comparisons and how you analyze the data, but that was always our belief or our hope. And the RATIFY trial ratifies that.

Eunice Wang, MD: I think it’s the first trial to show a positive benefit for this type of targeted agent, a tyrosine kinase inhibitor. I think ever since BCR-ABL inhibitors got developed for CML, there’s always been this belief of, could we develop a kinase inhibitor for acute leukemias?

Jorge E. Cortes, MD: And it’s actually fair to say that part of the reason why it takes so long is because the events were not happening as fast as they could.

Eunice Wang, MD: Right.

Alexander E. Perl, MD: Which is a good thing, and this is a high-risk population.

Jorge E. Cortes, MD: It’s a good thing. So, you know it took very long, but it was a good thing, because now we have this population of high-risk patients—and all of a sudden, we’re not having the rate of events that we thought we would be having.

Transcript Edited for Clarity 
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