Recent Advances in Treatment of Acute Myeloid Leukemia - Episode 12

Second-Generation FLT3 Inhibitors for AML


Harry Erba, MD, PhD: Naval, what are some of the unmet needs, then, for the FLT3- and ITD-mutated patients?

Naval Daver, MD: Everything is still an unmet need. We’re making progress incrementally, which is great. That’s absolutely happening. As Mark already discussed, the midostaurin frontline RATIFY study improves survival incrementally, yes, but conceptually it’s very important and with transplant is doing well. We do see a number of relapses at the end of the day when you look at long-term survival, 5-year survival, it’s still in the range of 50% to 55%. We do see relapses in these patients.

What’s changing though is the nature of these relapses molecularly. We’re seeing this a lot at [The University of Texas] MD Anderson [Cancer Center], and other centers are seeing the same: a number of these people were initially FLT3 mutated when they got induction with the FLT3 inhibitor and more, so when they’re getting transplant, when they’re relapsing, they are now FLT3 undetectable. This gets back to the point that we previously discussed: it’s critical to check the FLT3-mutation status at the time of relapse or refractory status before moving to the next-generation FLT3 inhibitor like gilteritinib or quizartinib.

Mark Levis, MD, PhD: But in the same context, the other…

Naval Daver, MD: The other side is very, very true, and that’s even more important to us because you could have up to 20%, on some of the recent analyses, of people who did not have a detectable FLT3. I use the word detectable because I will not say acquired. We don’t know if this is selection versus true acquisition. There’s a lot of research work there. We see 20% who may have a detectable new FLT3 mutation at relapse that was not there before. For this 20%, you open a very nice, oral effective therapeutic option: gilteritinib, other combinations, and drugs like quizartinib. These are critical things to think about.

Frontline, we’re hoping that, with QuANTUM-First, which is a study using quizartinib with induction versus induction, we would see further improvement. We’re going to end up, no matter what we say, comparing trials and looking at EFS [event-free survival] here and here and OS [overall survival] here and here. The studies are a little different because QuANTUM-First allows patients up to 75 years old, whereas midostaurin, in the RATIFY study, was up to 60 years old, so all those subsets and real-world analyses will happen. The hope is that quizartinib—a highly potent, more selective, probably the most potent FLT3 in the lab pound for pound—will show a much better EFS, OS [overall survival] end point. That’s the hope. It may not pan out. Then the question will start emerging: do we adopt this strategy and how that further changes because I think it will further change the relapse FLT3 outcomes.

Harry Erba, MD, PhD: The QuANTUM-R study was a positive study.

Naval Daver, MD: Yes.

Harry Erba, MD, PhD: It was quizartinib versus chemotherapy, intensive or less intensive, but there was an improvement in median survival, which was the primary endpoint of the study. Unfortunately, just like the ADMIRAL trial, which we’ll talk about in a second, with gilteritinib, the survival of 2 years is very poor in both groups, but it improved the median survival. More patients got into remission, more patients were bridged to transplant, yet it wasn’t approved.

Mark Levis, MD, PhD: With an oral agent as opposed to chemotherapy.

Harry Erba, MD, PhD: We’ll talk a bit about how patients did after transplant in a second. Mark, why wasn’t it approved?

Mark Levis, MD, PhD: It was approved in Japan and, as I was talking with Japanese colleagues, they were absolutely baffled at why it was not. They were like, “What is going on over there?” It was not something they’re used to seeing. No, the concerns raised by the regulatory agencies. Some of them raised what I would regard as scientifically invalid concerns about safety, which were—and I’ll go on record—scientifically invalid. The primary concern was there was that there was a subset of patients who were not followed for survival. They left the trial, and their local investigator didn’t keep track of them, so that was a significant fraction. They found out that they were randomized to get chemotherapy, so they made a beeline to get another FLT3 inhibitor. It’s like when someone moves, and the person didn’t say “Simon says.” They got them—aha, got you, your trial is invalid. Perfectly good drug and a good outcome, but we’ve got you.

Harry Erba, MD, PhD: That happened in a significant number, it was a quarter of patients randomized to chemotherapy who came off study compared with only like 10% to 15% in the ADMIRAL trial.

Naval Daver, MD: Oh, yeah. Yeah.

Mark Levis, MD, PhD: The regulators were concerned we did not have equipoise. No, we didn’t have equipoise. No one wants to give a relapsed/refractory FLT3- or ITD-mutant patient chemotherapy, and the patients knew that, yet this was the trial that we all had to do, so there it is.

Harry Erba, MD, PhD: The other issue that came up at ODAC [the FDA’s Oncologic Drugs Advisory Committee] was the QT prolongation.

Mark Levis, MD, PhD: I would regard that as scientifically invalid. Absolutely, there is QT prolongation, and there is this concept that there are sheets of patients dying from torsades, which doesn’t happen. I found it instructive that Japanese academic colleagues, who may now have the drug, were looking at us and laughing.

Harry Erba, MD, PhD: It targets only the ITD patients, and it’s been out there that patients getting quizartinib, targeting ITD, may relapse with a TKD mutation. Is there a benefit of targeting just the ITD, or is it undermined?

Mark Levis, MD, PhD: There is. The real role of the drug is in what’s going to be shown in QuANTUM-First. I want the drug up front because that’s what you need to hammer. In the setting of chemotherapy, I think this drug will work better. When you add therapies together, you’re going to be able to presumably prevent the emergence of the TKD. There’s no question: they will emerge, and we have gilteritinib to address that when that happens.

Harry Erba, MD, PhD: The QuANTUM-First study has completed accrual. It’s going to be a coprimary end point of EFS and OS, right? Unfortunately, we’re not going to have the results for a couple of years.

Rami Komrokji, MD: One of the things that, when I saw the results from the studies, was that we should not be offering those patients chemotherapy in that setting of FLT3-relapse. When they look at the response rates below 10%, you start asking “Why am I doing that?”

Mark Levis, MD, PhD: Absolutely.

Naval Daver, MD: It’s very important, what Mark said, this equipoise. This is not the first time it happened. After this ODAC, I was discussing with some of our colleagues that these are exactly the same numbers with imatinib. If you go back and look, about 23% of people did not go on to randomized arms because we knew BCR-ABL therapy is effective. It’s almost unfair to say we have to blind ourselves and go back after you know something that you’ve treated 100 times is effective. Hopefully, QuANTUM-First comes out very positive, and we’ll get both drugs because we need both drugs at the end of the day.

Transcript Edited for Clarity