Combinations are the Future in FLT3-Mutated AML - Episode 6
Naval G. Daver, MD, reviews the safety and efficacy of quizartinib in relapsed/refractory acute myeloid leukemia as seen in the phase 3 QuANTUM-R study.
Naval G. Daver, MD: As you mentioned, I think quizartinib is a FLT3 inhibitor that went under the radar in the last 1, 1.5 years. Unfortunately, it did not get the FDA approval in the US and Europe. It was only approved in Japan. But I think that this is a very potent FLT3 inhibitor. We’ve seen the preclinical data. Pound for pound, quizartinib is probably the most potent in the laboratory. This is a type 2 FLT3 inhibitor, so it does not target the TKD [tyrosine kinase domain] or D835 mutations. We know that the escape can be through acquisition of TKD or D835. But the large, randomized, multinational phase 3 study that was done with this drug was called the QuANTUM-R study. R stands for relapse. There is also a QuANTUM-First study exploring the drug in the frontline setting. That trial just completed enrollment 6 months ago, and we hope to have data later this year.
QuANTUM-R looked very similar to the ADMIRAL study of gilteritinib. It is for ITD [internal tandem duplication] only here because we know quizartinib does not work for TKD mutations. So this study randomized patients to receive outpatient quizartinib single-agent oral therapy versus investigator’s choice, which was either intensive FLAG-IDA [fludarabine, cytarabine, G-CSF, idarubicin] or MEC [intermediate-dose cytarabine] or low-intensity therapy. The primary end point was survival. Basically, the study showed that quizartinib as a single agent did improve overall survival to 6.5 to 7 months versus about 4, 4.5 months with the chemotherapy arms. In fact, the P value was significant. And when you look at the remission rates, these were about 48% CRc [complete composite remission], all marrow remissions, versus about 25%. So on all aspects, it looked like quizartinib did beat chemotherapy. There were some questions about the therapeutic equipoise, meaning that physicians may have known that certain patients were getting quizartinib and had preferred them, to some extent. I personally don’t think this happened, but there were a number of patients in question.
And also, quizartinib has a QTc [corrected QT interval] signal. I think this is something that is of concern to the FDA and the community. In our big centers, we’re good at monitoring this. We know the EKG [electrocardiogram] frequencies. We will adjust drugs, etc. But that issue could become significant in the community. So for all these reasons and many other discussions, it unfortunately did not get approval. But we’re hoping that with the QuANTUM-First study, which I think is a better-designed study, well-run, it hopefully will show that quizartinib added to induction chemotherapy significantly improves both event-free and overall survival over standard induction. We will get those results in a few months. I think it will be great to have multiple FTL3 inhibitors, just like we do for CML [chronic myeloid leukemia].
Jessica K. Altman, MD: I agree. Can you speak a little about how you’ll interpret the data from QuANTUM-First given the standard arm, and how you’ll compare that in your mind? Let’s assume it’s going to be a positive study. I’m very excited to be able to have that drug in my armamentarium. But help me interpret that as I’m talking to an insurance company, thinking about quizartinib versus midostaurin.
Naval G. Daver, MD: Yes, exactly. This is going to be a bit of a challenge. When the QuANTUM-R 3+7 [daunorubicin, cytarabine] with quizartinib versus 3+7 [daunorubicin, cytarabine] was designed in 2012, and midostaurin, we didn’t know the data. Obviously, we didn’t know if it would be positive. And so, this was the FDA regulatory agreement. And as you said, I would be very surprised if this was not positive. But let’s say, yes, it’s positive. Then what do we do? We have 3+7 [daunorubicin, cytarabine] with quizartinib as better than 3+7 [daunorubicin, cytarabine], and 3+7 [daunorubicin, cytarabine] with midostaurin as better than 3+7 [daunorubicin, cytarabine]. But what about the comparison? So I think this is going to go into a lot of cross-trial comparisons. People are going to look at the true CR [complete response] and CRc rates. We will have molecular data from the quizartinib data set. There will be PCR [polymerase chain reaction] and flow, and that will be compared to some of the subsets of midostaurin for which we had recent papers looking at some of these separate subsets.
Then I think in the end, people are going to look at the survival curve, right? If we see 75%, 80% survival at 4 years, even though it’s a different trial in a different time period, I think most people would say, "Well, this looks good enough for me." If they look very similar, I think it’s going to be a question mark whether one needs to do a randomized phase 2 smaller study of 3+7 [daunorubicin, cytarabine] and quizartinib versus 3+7 [daunorubicin, cytarabine] and midostaurin. I think there is a lot of political and economic pushback from both sides. I think the NCCN [National Comprehensive Cancer Network] and the FDA will probably give both an acceptable status, and then people will have to decide. Then of course, the last thing that can be done is a real-world comparison. There are efforts being developed to look at the real-world outcomes of 3+7 [daunorubicin, cytarabine] and midostaurin and then trying through some form of propensity-matching or other comparison to compare those data to the QuANTUM-First data set. So hopefully with all of these, we will get an answer. But it will take many years, probably.
Jessica K. Altman, MD: Those are great points.
Transcript Edited for Clarity