Beyond Midostaurin: Advances Continue With FLT3 Inhibitors in AML

Jorge Cortes, MD

Midostaurin (Rydapt) was approved in April 2017 for the treatment of adult patients with newly diagnosed FLT3-positive acute myeloid leukemia (AML) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

Although this approval was a breakthrough in a field that has seen little progress until now, there is still room to do even better, says Jorge E. Cortes, MD.

In a dose-escalation study of the FLT3 inhibitor crenolanib presented at the 2017 European Hematology Association (EHA) Congress, investigators are looking to find the maximum-tolerated dose of the agent when combined with high-dose cytarabine plus idarubicin in patients with relapsed or refractory FLT3-internal tandem duplication (ITD). Though currently ongoing, crenolanib is showing activity and tolerability.

Other FLT3 inhibitors also under development are quizartinib in the ongoing phase III randomized QuANTUM-R study, and gilteritinib.

In an interview with OncLive at EHA, Cortes, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discussed the study of crenolanib—on which he is the lead author—and the impact of FLT3 inhibitors in AML.

OncLive: Please provide an overview of your study.

Cortes: The study is a dose-escalation study of crenolanib—which is a very potent oral FLT3 inhibitor—and we are combining it with standard chemotherapy of cytarabine/idarubicin. We are trying to find the right dose for this combination—that it provides adequate safety. So, we are going through different dose levels of crenolanib, from 60 mg to 80 mg to 100 mg three times a day.

At the moment, that is what is being presented. Eventually, this study will have an expansion arm for the ones that reach maximum-tolerated dose and recently, the study has also been amended to include other combination chemotherapy regimens. Those are just starting now.

What are the significant results thus far?

The main thing that we can say now about this study is that it showed that you can safely combine crenolanib at the standard dose of single agent, with a full dose of cytarabine and idarubicin. That means that we did not see any excess of toxicities; of course, the chemotherapy is very myelosuppressive and that did not change, but the duration of myelosuppression was not different. There were no additional risks of infection from bleeding; there were no more gastrointestinal toxicities. So, we can safely go to the full dose.

We have seen good responses in some patients. These are patients who are relapsed/refractory and are actually very heavily pretreated. Yet, even in that context, we have seen several patients achieve a response, even with the lower doses of crenolanib.

What do you think the next steps with this FTL3 inhibitor should be?

Crenolanib definitely has activity, it has some properties that are very attractive. There are many FLT3 inhibitors being developed, and this is what you'd call a type 1 inhibitor—which is effective against the FLT3-ITD mutation, but also against the kinase domain mutation. So, that is a potential advantage over some of the drugs that only work against the ITD.

I think the next important steps are to demonstrate in a randomized fashion, that combining crenolanib with some sort of standard chemotherapy, be it the one we are discussing now, or one with hypermethylating agents, which we’ve done also. Many of these studies have started so they are not being presented yet. But, that is the next step to confirm the efficacy and if that is the case, get the drug approved for that indication.

The study is ongoing—it is adding other combinations. We are going to test it with fludarabine, with MEK—which are common salvage regimens. We are also going to start investigating it in combination with gemtuzumab ozogamicin—an anti-CD33 monoclonal antibody—so a different approach to see if it generates some synergy.

Could you discuss the differences between midostaurin and the second-generation FLT3 inhibitors?

There are several FLT3 inhibitors, and the most common mutation is FLT3-ITD. There are many drugs that have been developed that have not proven to be very effective but there are several that are approved—such as midostaurin—or under development, such as quizartinib, crenolanib, and gilteritinib. We've had a lot of data already with these 3. And then there is sorafenib, which hasn’t been approved as a FLT3 inhibitor but is a very good FLT3 inhibitor.

The main difference between them is that we know for patients with PIK3-ITD that are treated with a FLT3 inhibitor, they may develop a mechanism of resistance—a kinase domain mutation. About 20% to 25% of patients have that as a mechanism of resistance. And we know that the treatment of any of these drugs as a single agent is transient—we do get good responses but they tend to be transient.

The benefit of some of these drugs—and crenolanib and gilteritinib are notable for these—is that they have inhibitory activity against DA-35. We believe that these will decrease the mechanism of resistance and with crenolanib, we've shown data that hasn't shown emergence of DA-35 as a mechanism of resistance. That is an important differentiating factor between some of these drugs.

Of course, the toxicity profile is different for different drugs, and that is another factor that we are trying to determine what the key safety issue is for each drug. For example, quizartinib has QTC prolongation, and with crenolanib, there is a little bit of GI toxicities but only grade 1/2—it’s really well tolerated, there is not QTC prolongation.

What do you believe to be the biggest challenge in the treatment of FLT3-positive AML?

We had midostaurin approved, and the setting where it was approved was frontline therapy in combination with standard chemotherapy 3+7, where it showed a survival benefit when you combine it with a chemotherapy versus chemotherapy alone. However, the benefit was only modest. The survival benefit was good and very welcome, but still, a significant number of patients relapsed and died.

This means we need to investigate other mechanisms of resistance. How do these cells escape the inhibition of the FLT3 activation? We do we know that some of these patients when they relapsed they usually have other molecular abnormalities, other cytogenetic abnormalities. I think the challenge would be to figure out how to combine inhibitors, are there other targets, are there other approaches—so that we can build upon what we already achieved with midostaurin, which I think was very good, but we need to make that even better. It’s good, but we still have a lot of room for improvement.

We also need to investigate hypermethylating agents; there are studies that suggest combinations with this could benefit older patients. Several of these drugs have been tested in combination with hypermethylating agents and they seem to have good results; so, in bringing that to the frontline with older patients who cannot take standard chemotherapy, we just have to demonstrate the benefit like we did with the midostaurin trial.

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