Transcripts: Daniel A. Pollyea, MD, MS: Quizartinib is among the most specific of the specific FLT3 inhibitors, and so we’re very excited about the potential for quizartinib to have an impact in FLT3-positive AML [acute monocytic leukemia] patients. I think the data that Dr Cortez presented was very encouraging. What he showed is that in relapsed and refractory FLT3-positive AML patients randomized to receive quizartinib as a single agent versus standard chemotherapy-type options, there was a significant benefit with respect to overall survival in the patients who received quizartinib.
And you know that’s a really significant accomplishment given the toxicity profile of quizartinib compared with chemotherapy. I think it’s very clear what a patient would prefer and what practitioners would prefer to do. And even sparing the patient the toxicity, patients still live with quizartinib. So a really significant accomplishment.
I do want to point out that the survival, while significantly better, was still relatively short, and for clinical significance I think we still have to understand a difference of weeks or a month. And so I think it’s a better option, and I think we all look forward to using it, but I think we also have to think about how to do even better.
Relapse after a FLT3 inhibitor is a given. So you know if a patient can be bridged to a transplant, which can be a curative strategy, then that I think should be done. FLT3 is a late mutation. And effective targeting of FLT3, doesn’t really do much to eradicate the disease, but it can get the bulk of the disease under control for some period of time. It seems to be probably in most cases a short period of time when this is used as a single agent. So you know when you use a FLT3 inhibitor as a single agent in relapsed and refractory patients, you can expect relapse, unless your goal is to bridge a patient to a transplant. Even then, the relapsed risk would be very high. But that’s the only scenario in which there’s a chance that a relapse might not occur.
One of the biggest resistance mechanisms to FLT3 inhibitors seems to be through the development of a tyrosine kinase domain mutation in the FLT3. And that’s been a well-understood resistance mechanism for a very long time to FLT3 inhibitors. We’re getting more information now in the era of these very specific FLT3 inhibitors, and I think we’ll soon understand a lot more about mechanisms of resistance.
Naval G. Daver, MD: At this time, based on the ratified data in the frontline setting, it is recommended that we check all patients for FLT3 mutation and try to those results within a few days. And if there’s a FLT3 mutation that is found positive, whether an ITD [internal tandem duplication or a] TKD [tyrosine kinase domain], whether high or low allele burden, we add midostaurin. And in fact, the benefit was shown across all of these different FLT3-mutation groups.
In the relapsed setting, similarly, the QuANTUM-R study has established that FLT3 inhibition as single agent with a potent FLT3 inhibitor—namely, quizartinib—was superior, both doubling your CR [complete response] rates as compared with the high-dose chemotherapy and improving the overall survival and the number of people who go to transplant with a safer profile and an oral agent given to an outpatient.
So I think it is now established that we should use a FLT3 inhibitor in the salvage. Similarly, gilteritinib has shown that as a single agent with salvage, this was able to induce responses better than chemotherapy and was very safe. So you can choose between the quizartinib or the gilteritinib.
What has overall been shown to be very important is that the mechanism of action of quizartinib and gilteritinib seem to be slightly different. Quizartinib is very potent, and the responses that we saw with quizartinib were very quick within a median of 4 to 5 weeks. And this is because even preclinically, quizartinib does appear to be the most potent of all FLT3 inhibitors.
Gilteritinib is less potent, and the median duration to response was about 3 months, showing that we need to monitor these people for a longer time, not expect responses right away. The other difference is that gilteritinib does seem to have activity toward the TKD, or non-ITD mutations, which is not shown with quizartinib. So I think in our practice, if we have a pure ITD patient, and we want to get a response quickly and take them to transplant, it seems that quizartinib may be the most potent at doing that based on the emerging response kinetic profiles.
On the other hand, if you have an older patient, and you know you’re not rushing because they’re not proliferative and you have time, you could give them gilteritinib and wait, and more so if you have a patient who has a pure D835. Or maybe for a dual-ITD D835, you could consider using gilteritinib in that population. And eventually I think in practice we are going to be switching between these because most responses, unless the patients are transient.
Transcript Edited for Clarity