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Emerging FLT3 Inhibitors in 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: Monday, Mar 05, 2018



Transcript: 

Harry Erba, MD, PhD: Sasha, let’s move on to gilteritinib.

Alexander E. Perl: Quizartinib opened many doors. Unlike midostaurin, it had single-agent activity. It could get patients from relapsed disease to transplant. Many of these patients actually became long-term survivors, and that just hadn’t been seen with regularity previously. But 2 points came up that were an issue. You mentioned one, which was the issue of QT prolongation, and there were other toxicities, such as significant myelosuppression, associated with the drug. The other issue was the durability of the responses, and when we looked at why that happened, it was due to new mutations in FLT3. That’s kind of good, and that’s kind of bad. It tells you that you’re actually hitting FLT3 if you see a new mutation that confers resistances in the target of the drug, but the bad thing is that you need a drug that’ll hit it. That’s what led to newer FLT3 inhibitors. It would basically try to address those limitations, be both a potent FLT3-ITD and FLT3-D835 inhibitor and hopefully not have as many off-target effects that would cause problems in patients. That’s what led to the development of both crenolanib and gilteritinib, which are variations on a theme here.

These are type 1 inhibitors. If you remember, there are type 2 and type 1 inhibitors. BCR-ABL inhibitor imatinib is a type 2 inhibitor; dasatinib is a type 1 inhibitor. They have slightly different mutations that they have specificity for, and in this case, gilteritinib and crenolanib both have activity against ITD and the D835, which is potentially an advantage over quizartinib. It’s similarly potent in terms of inhibiting the kinase and is certainly selective. It has not led to a head-to-head comparison or really any randomized comparison but showed a single-arm demonstration of somewhat more durable responses to the single agent with really modest toxicity and not much in the way of evidence of QT prolongation, which has been encouraging.

Similarly, we have less in the way of myelosuppression with that drug in a noncomparison-based way of developing it in the phase I/II setting. It has not completed, but is close to completing, a comparison phase III study in the first-relapse setting against an investigator’s choice of salvage chemotherapy. It’s entering 3frontline therapy studies, one that’s combining it with induction chemotherapy, which is going to be presented at the ASH meeting. There are also studies looking at it in the maintenance setting, either after chemotherapy consolidation or after allogeneic transplant.

Harry Erba, MD, PhD: What about crenolanib, Eunice?
 
Eunice Wang, MD: Crenolanib, as Sasha mentioned, is a type 1 tyrosine kinase inhibitor. It was actually originally developed as a drug for brain tumors because it is highly specific for FLT3 but also has PDGFR. It doesn’t hit c-KIT, and it doesn’t hit AXL, which are some of the other kinases that some of the agents like gilteritinib do hit. It does hit TKD, so it does have that activity that is missed by quizartinib. This drug was really developed in the setting of all these other FLT3 tyrosine kinase inhibitors. It was really initially tested in the phase I study in patients who had failed all other FLT3 inhibitors, including off-label FLT3 inhibitors sorafenib, midostaurin, quizartinib, and even gilteritinib. There are patients—I think that, Sasha, you had one—who were just on one FLT3 tyrosine kinase inhibitor after another.

And so, the end FLT3 tyrosine kinase inhibitor for many of these patients was crenolanib. In a very, very heavily pretreated population of patients as a single-agent refractory/relapsed rate, it did have activity: 30%, 40%, or 50%. The agent is also different from the other FLT3 kinases and has a very short half-life. It’s very potent. It does block FLT3, but the half-life of the drug is about 6 to 8 hours. So it is a drug you take 3 times a day.

In further developing this, one would rather take a single-agent drug as a monotherapy for relapsed/refractory AML. Really, this might not be the best agent if you take something 3 times a day versus once a day and you have equal efficacy. It may not be the best thing. What the studies have been really doing with crenolanib is taking this very potent tyrosine kinase inhibitor that also covered a lot of very heavily pretreated resistance—a lot of FLT3 tyrosine kinase mutations that are associated with therapy resistance or other kinases—and moving it into the up-front setting.

At this ASH meeting, I’ll be presenting data on a smaller study, a phase II efficacy study, looking at using crenolanib similarly to the RATIFY study—in combination with cytarabine, anthracycline-based induction consolidation, and then maintenance—for newly diagnosed patients with an FLT3-mutant disease, so FLT3-ITD and FLT3-TKD. Now, it’s a very small study, with 44 patients, but it’s just focusing on the patients who were between the ages of 18 and 60 to make a clear comparison with the RATIFY trial in the same age group.

Overall, the response rates with the combination of crenolanib and cytarabine anthracycline-based chemotherapy—whether it be daunorubicin or idarubicin—were very high. Overall, there were CR/CRi rates of about over 80% after 1 or 2 cycles. Overall survival was at a median of about 17+ months at about 79%. There was a cumulative rate of relapse of about 16%. Now, there was a very small number of patients. We’re talking about 29 patients. But those numbers, at least initially, compare favorably with some of the RATIFY data. That agent is, I think, also going into—just like the quizartinib compound—up-front trials, comparing it with the new standard of care, midostaurin.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: Sasha, let’s move on to gilteritinib.

Alexander E. Perl: Quizartinib opened many doors. Unlike midostaurin, it had single-agent activity. It could get patients from relapsed disease to transplant. Many of these patients actually became long-term survivors, and that just hadn’t been seen with regularity previously. But 2 points came up that were an issue. You mentioned one, which was the issue of QT prolongation, and there were other toxicities, such as significant myelosuppression, associated with the drug. The other issue was the durability of the responses, and when we looked at why that happened, it was due to new mutations in FLT3. That’s kind of good, and that’s kind of bad. It tells you that you’re actually hitting FLT3 if you see a new mutation that confers resistances in the target of the drug, but the bad thing is that you need a drug that’ll hit it. That’s what led to newer FLT3 inhibitors. It would basically try to address those limitations, be both a potent FLT3-ITD and FLT3-D835 inhibitor and hopefully not have as many off-target effects that would cause problems in patients. That’s what led to the development of both crenolanib and gilteritinib, which are variations on a theme here.

These are type 1 inhibitors. If you remember, there are type 2 and type 1 inhibitors. BCR-ABL inhibitor imatinib is a type 2 inhibitor; dasatinib is a type 1 inhibitor. They have slightly different mutations that they have specificity for, and in this case, gilteritinib and crenolanib both have activity against ITD and the D835, which is potentially an advantage over quizartinib. It’s similarly potent in terms of inhibiting the kinase and is certainly selective. It has not led to a head-to-head comparison or really any randomized comparison but showed a single-arm demonstration of somewhat more durable responses to the single agent with really modest toxicity and not much in the way of evidence of QT prolongation, which has been encouraging.

Similarly, we have less in the way of myelosuppression with that drug in a noncomparison-based way of developing it in the phase I/II setting. It has not completed, but is close to completing, a comparison phase III study in the first-relapse setting against an investigator’s choice of salvage chemotherapy. It’s entering 3frontline therapy studies, one that’s combining it with induction chemotherapy, which is going to be presented at the ASH meeting. There are also studies looking at it in the maintenance setting, either after chemotherapy consolidation or after allogeneic transplant.

Harry Erba, MD, PhD: What about crenolanib, Eunice?
 
Eunice Wang, MD: Crenolanib, as Sasha mentioned, is a type 1 tyrosine kinase inhibitor. It was actually originally developed as a drug for brain tumors because it is highly specific for FLT3 but also has PDGFR. It doesn’t hit c-KIT, and it doesn’t hit AXL, which are some of the other kinases that some of the agents like gilteritinib do hit. It does hit TKD, so it does have that activity that is missed by quizartinib. This drug was really developed in the setting of all these other FLT3 tyrosine kinase inhibitors. It was really initially tested in the phase I study in patients who had failed all other FLT3 inhibitors, including off-label FLT3 inhibitors sorafenib, midostaurin, quizartinib, and even gilteritinib. There are patients—I think that, Sasha, you had one—who were just on one FLT3 tyrosine kinase inhibitor after another.

And so, the end FLT3 tyrosine kinase inhibitor for many of these patients was crenolanib. In a very, very heavily pretreated population of patients as a single-agent refractory/relapsed rate, it did have activity: 30%, 40%, or 50%. The agent is also different from the other FLT3 kinases and has a very short half-life. It’s very potent. It does block FLT3, but the half-life of the drug is about 6 to 8 hours. So it is a drug you take 3 times a day.

In further developing this, one would rather take a single-agent drug as a monotherapy for relapsed/refractory AML. Really, this might not be the best agent if you take something 3 times a day versus once a day and you have equal efficacy. It may not be the best thing. What the studies have been really doing with crenolanib is taking this very potent tyrosine kinase inhibitor that also covered a lot of very heavily pretreated resistance—a lot of FLT3 tyrosine kinase mutations that are associated with therapy resistance or other kinases—and moving it into the up-front setting.

At this ASH meeting, I’ll be presenting data on a smaller study, a phase II efficacy study, looking at using crenolanib similarly to the RATIFY study—in combination with cytarabine, anthracycline-based induction consolidation, and then maintenance—for newly diagnosed patients with an FLT3-mutant disease, so FLT3-ITD and FLT3-TKD. Now, it’s a very small study, with 44 patients, but it’s just focusing on the patients who were between the ages of 18 and 60 to make a clear comparison with the RATIFY trial in the same age group.

Overall, the response rates with the combination of crenolanib and cytarabine anthracycline-based chemotherapy—whether it be daunorubicin or idarubicin—were very high. Overall, there were CR/CRi rates of about over 80% after 1 or 2 cycles. Overall survival was at a median of about 17+ months at about 79%. There was a cumulative rate of relapse of about 16%. Now, there was a very small number of patients. We’re talking about 29 patients. But those numbers, at least initially, compare favorably with some of the RATIFY data. That agent is, I think, also going into—just like the quizartinib compound—up-front trials, comparing it with the new standard of care, midostaurin.

Transcript Edited for Clarity 
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