Gilteritinib is a selective and potent FLT3 inhibitor. It’s a type 1 inhibitor so it’s active both against FLT3-ITD mutations and also the tyrosine kinase domain or TKD mutations that are both common in AML. The FLT3-ITD mutations have been really problematic because they are associated with high rates of relapse but if either are present at relapse patients have really dismal outcome, very short survivals and poor responses to salvage chemotherapy. So this has been a low-hanging fruit for drug development in terms of developing tyrosine kinase inhibitors but to date none of them has really stuck in terms of having a long-term outcome in patients with relapsed refractory disease because of a number of limitations. Either they weren’t potent enough or they had toxicity issues or they led to resistance in the FLT3 receptor itself. So we would see patients with FLT3-ITD mutations who would respond to a drug and then lose response by developing a TKD mutation. That’s where gilteritinib was developed to cover all of those bases to be a well-tolerated drug with activity against all of the mutations.
On the ADMIRAL study we put it head to head against standard salvage chemotherapy in the population of patients with either refractory AML with FLT3 mutation or relapsed disease after a prior CR. So this was a phase III study, 371 patients enrolled to it and they were randomised 2:1 to either single agent gilteritinib or investigator’s choice of standard chemotherapy, either high intensity chemotherapy, reinduction therapy, MAC or FLAG-IDA or low dose cytarabine or azacitidine as the low intensity options which were chosen prior to randomisation.
The primary endpoints of the study actually were co-primary endpoints of response in the gilteritinib arm which really was just used for regulatory submission. But the primary endpoint of the study was overall survival and the study actually showed not only higher response rates in the gilteritinib arm but also improved survival in that group as well. The median survival for the chemotherapy group was 5.6 months and it was 9.3 months in the gilteritinib arm. This is notable because it’s a molecularly targeted agent – for the first time in the relapsed/refractory setting we’re actually showing that picking a mutation and then targeting it leads to better outcomes. So that’s noteworthy that really FLT3 inhibitors are the only drugs for which we’ve shown this kind of benefit in terms of using a targeted drug and showing an overall survival benefit in the phase III setting.
The drug was also submitted for regulatory approval, as I mentioned, and was approved in the US and also in Japan in the past year.
The main thing we see are cytopenias which has been true of a number of drugs targeting FLT3. It’s a haematopoietic cytokine receptor so it regulates haematopoiesis and how many blood cells are made daily so that’s not entirely surprising. The other things we can see are largely asymptomatic laboratory value abnormalities – we can see LFT abnormalities with some regularity and those were seen, actually, a little bit more frequently in the gilteritinib arm than the chemotherapy arm. But overall if you looked at all the toxicities there were fewer serious toxicities in the gilteritinib arm when corrected for drug exposure because patients took gilteritinib much longer than chemotherapy, largely because they responded to it more frequently, and then just stayed on study until either intolerance or progression.
There were a few toxicities we need to monitor for in the drug and in its approval there’s recommendations for monitoring of QT prolongation which was not very common but did occur in some patients. There’s also some risk of CK elevation, some risk of differentiation syndrome and a few patients had elevations of lipase with relatively few patients who had pancreatitis. There’s also language regarding PRES or posterior reversible encephalopathy, again very rare but if it happens it’s serious.
The message is there’s a new standard of care for relapsed/refractory patients with FLT3 mutation which means we have to find them. So the thing that’s notable about FLT3 is it’s often retained at relapse or in patients who are refractory to induction but there are times when that actually changes, that the patients didn’t have a FLT3 mutation when initially diagnosed and then it shows up at relapse. Clinically the way you spot that is when patients have a rapidly rising white blood cell count that’s when we tend to see these mutations. They can be lost also so it’s worth retesting at relapse because if you look at the response rate of the drug in phase I/II testing where we did not require patients to have a FLT3 mutation it was really quite low in patients who didn’t have FLT3 mutation. So there really is only a benefit in the mutated patients.
