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EHA 2021 | Novel FLT3 inhibitors for AML

Amir Fathi, MD, MPH, Massachusetts General Hospital Cancer Center, Boston, MA, gives an overview of the Fms related receptor tyrosine kinase 3 (FLT3) inhibitor landscape for the treatment of acute myeloid leukemia (AML), in particular commenting on the development of novel FLT3 inhibitors. Low specificity and low potency of initial FTL3 inhibitors necessitated the development of the next generation of FLT3 inhibitors, including gilteritinib, quizartinib and crenolanib. Although many FTL3 inhibitors have been approved for treatment, patients often relapse and require further FTL3 inhibitor treatment. Dr Fathi discusses the mechanism of action of a novel irreversible FTL3 inhibitor, FF-10101 and describes promising clinical results from a dose-escalation study (NCT03194685) in patients with relapsed/refractory primary or secondary AML. This interview took place at the virtual European Hematology Association (EHA) Congress 2021.

Transcript (edited for clarity)

As probably many of your audience are aware, FLT3 inhibitors have been under development now for, I would say more than a decade. With the initial set of FLT3 inhibitors being less specific, less potent, more promiscuous, in terms of their targets. Leading to not the most potent inhibition of the aberrant FLT3 receptor tyrosine kinase, and some, off-target effects related to the non-specific nature of those first-generation of FLT3 inhibitors, leading to some toxicity, predominantly GI and hepatic, and also skin...

As probably many of your audience are aware, FLT3 inhibitors have been under development now for, I would say more than a decade. With the initial set of FLT3 inhibitors being less specific, less potent, more promiscuous, in terms of their targets. Leading to not the most potent inhibition of the aberrant FLT3 receptor tyrosine kinase, and some, off-target effects related to the non-specific nature of those first-generation of FLT3 inhibitors, leading to some toxicity, predominantly GI and hepatic, and also skin.

And some of these early generation FLT3 inhibitors were lestaurtinib, midostaurin, sorafenib. More recently efforts have been made to develop more potent, selective, next generation FLT3 inhibitors and these have entered clinical trials in the last several years. Among these are gilteritinib and quizartinib, as well as crenolanib. Each have their own properties in terms of the inhibition profile and toxicity profile. Gilteritinib was recently approved by the FDA for relapse/refractory disease, but that hasn’t, er, these approvals of midostaurin and an earlier generation FLT3 inhibitor was also approved for newly diagnosed disease in combination. But these approvals have not necessarily stopped the development of FLT3 inhibitors for patients, because once patients are treated with an upfront FLT3 inhibitor, then they relapsed with another FLT3 inhibitor and in this case, most likely gilteritinib. Most of those patients, ultimately again progress and need additional FLT3 inhibitor therapy.

Which brings us to this particular abstract which is a very potent selective FLT3 inhibitor from Fujifilm. And it is active against FLT3 wild-type, FLT3-ITD and multiple FLT3 tyrosine kinase domain and gatekeeper mutations. It works by covalent binding, of the FLT3 receptor tyrosine kinase, that’s sort of its unique characterization. This was a dose escalation study, which revealed that the drug was relatively well tolerated. There were patients that on the study that had some cardiac toxicity, which was raised, but this did not ultimately impact finding a safe and well-tolerated dose, which ranged between 50 milligrams and 75 milligrams.

Among the 30 or so, I don’t remember off the top of my head right now, when I say 33 I might be inaccurate about that, but among the 30 or so patients that were treated most of which were heavily pretreated, FLT3 mutated patients, about five patients had a response with multiple complete remissions with incomplete recovery, such as CRh, CRp, CRi and ultimately the dose of 50 to 75 milligrams twice daily was deemed to be the recommended Phase II dose of this study.

So, I think there was an efficacy potential for this drug. It demonstrated some clinical promise. We will have to see whether it potentially can play a role in subsequent clinical studies for patients who have progressed beyond the initial line for FLT3 inhibitor therapy.

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