Glasdegib, Gilteritinib, and Quizartinib Against AML
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Daniel A. Pollyea, MD, MS: The FDA recently approved glasdegib with low-dose cytarabine for unfit, older patients—the older patient unfit for intensive chemotherapy. This is an interesting study, and it was not one that many people expected to see approved. The study took that population of patients and randomized them to receive low-dose cytarabine alone or low-dose cytarabine plus glasdegib. And glasdegib is a really interesting molecule. It inhibits something called smoothened, which is a part of the signaling pathway in cells called the hedgehog signaling pathway. Signaling pathway is typically quiescent, or not activated in cells after birth, so this is very much involved in fetal development of like limbs and fingers and things like that. And then once that’s all done after fetal development, those pathways get silent in most human cells.
Cancers have found ways to hijack this pathway and reactivate it to fuel their growth, and so it seemed logical that perhaps targeting an element of that signaling pathway—in this case, the protein smoothened—you could sort of abrogate that activity and allow for the cancer cell to be affected. And this strategy works in other cancer types. There are some other approvals for glasdegib-type drugs, but this was the biggest effort to look at glasdegib in leukemia.
And when they looked at this randomized study, low-dose cytarabine versus low-dose cytarabine plus glasdegib, they found a survival benefit. I think there are lots of criticisms of this study. First of all, low-dose cytarabine is not really the standard of care that most US practitioners would use for this patient population. Second, the control arm that received low-dose cytarabine did exceptionally poor—people have said that patients did worse than they would have expected for patients who otherwise would get low-dose cytarabine. So, you know, I think it’s an option for patients now. It’s FDA approved. It met its primary endpoint of survival. But it still remains to be seen…how this will be taken up into general practice.
Naval G. Daver, MD: So, gilteritinib was recently approved—in fact, just a few days ago—for patients with relapsed refractory FLT3-mutated AML [acute myeloid leukemia]. This included patients who have a FLT3-ITD mutation, a FLT3-TKD, or tyrosine kinase domain mutation, or those who have a dual mutant FLT3-ITD and [FLT3-]TKD.
The approval was based on an interim analysis of a recently completed phase III study, and it looked at 138 patients who received single-agent gilteritinib in the relapsed setting. These are patients who had relapsed AML and could have failed induction chemotherapy or HMA [hypomethylating agent]–based chemotherapy—any pathway to relapse was accepted. And the overall response rate…was very specifically defined as a CR[complete remission]/CRh [CR with partial hematologic recovery]. So this was a complete remission or complete remission with incomplete immunological recovery.
The CRh basically means that the patients called their platelets above 50 but not all the way above 100 —that would be required for CR—or that they got their ANC [absolute neutrophil count] above 0.5, but not all the way above 1. So they still did have to have some hematological recovery, which is important to know, because in the past, when we reported some of response rates, we used to use CR/CRi [CR with incomplete blood count recovery], which could include all responders with less than 5% RAS without any count recovery.
So based on these data, we think the CR/CRh that was achieved, which was 21%, was actually quite encouraging. There have been a number of historical studies, as well, such as a recently completed relapsed study of quizartinib versus chemo that showed that chemo is extremely ineffective with response rates of 10% or less when we’re thinking about CR/CRh in this relapsed population.
So, now you have a drug that is oral, much better tolerated, can be given outpatient, and seems to give you maybe double of the CR/CRh rates that you would get with chemotherapy, and more people to go to transplant. So it truly is a win-win situation, and I think when both caotripinib and, within some time, quizartinib is approved, those will be the drugs to use in the relapsed setting over chemotherapy.
There are 2 main types of FLT3 mutations, the FLT3-ITD and the FLT3-TKD. About 80% of AML will have the FLT3-ITD, and about 15% will have both FLT3-ITD and [FLT3-]TKD, and about 5% will have FLT3-TKD alone.
There are 2 types of FLT3 inhibitors. There are those that inhibit predominantly the FLT3-ITD. These are drugs like sorafenib and quizartinib. And quizartinib especially among these is extremely very potent. And then there are the drugs that are targeted against both ITD and TKD, or TKD alone. These include midostaurin, crenolanib, and gilteritinib. So gilteritinib, which has now been approved, does have preclinical activity suggesting high activity against ITD for sure but also against the TKD mutant.
Now, in the trials that were done, the CHRYSALIS and the ADMIRAL studies, there was a small group—a handful of TKD patients, about 24—and there were some responses seen with them. Two of the patients had a response. So we’re not sure if in the isolated TKD, gilteritinib will maintain its activity or maybe even when it’s combined with other agents, we will see better activity. But in the patients who had the dual mutant, which included about 50 to 60 patients in these 2 studies, we are seeing the 40% to 45% CR/CRi response rates. So we do feel that if you have a double mutant, we may favor gilteritinib in that population over quizartinib.
The QuANTUM-R study was a randomized phase III multinational study that looked at patients who had first relapsed or primary refractory acute myeloid leukemia with a FLT3 mutation. It’s very important to notice that this study actually took people who we would consider very high risk, or adverse profile, because these were patients who had a remission less than 6 months or were primary refractory. And these are the patients who invariably do not respond much to chemotherapy or epigenetic therapy in salvage. So the study randomized 360 patients to receive quizartinib alone versus investigator choice therapy, which would have been low-dose treatment like low dose cytarabine, azacitidine, or high-intensity treatment like FLAG-IDA [fludarabine, cytarabine, idarubicin, and G-CSF], MEK inhibitor, chemotherapy.
The primary endpoint of this study was overall survival. That study met its primary endpoint of overall survival with the quizartinib as a single agent showing superior overall survival compared with chemotherapy, FLAG-IDA, MEK, or the low-intensity therapy. And now it’s established in relapsed FLT3-mutated AML that we should be using quizartinib as a FLT3 inhibitor, or gilteritinib, but not chemotherapy.
What was really striking from the study was that in the patients who received chemotherapy, not only were the response rates lower than with quizartinib—they were 25% versus 50%—but the true CR rate was just 1%, basically again proving the fact that in those patients who have an early relapse within 6 months and are primary refractory, giving subsequent chemotherapy is almost useless. And really, these are the patients where targeted therapy seems to work.
Now we think that with a single-agent quizartinib, although it did improve the survival, it was a small increment—but the question is if you can…now combine quizartinib with other epigenetic agents, which we are doing in our institution, and showing that that could further improve response rates and survival significantly. So I think the study is very important proof of concept to get the drug approved and establish the FLT3 inhibition and relapse like the RATIFY trial did in the front-line study as the path forward.
Quizartinib in general has been very safe and well tolerated. One of the concerns that we’ve had in the past based on published reports and our experience has been the QTc [corrected QT interval] prolongation. It’s important to know that this was noticed in an issue of phase I studies where we were escalating to very high doses of 150 to 180 quizartinib. In the current doses in the phase 3 and the approved doses that will be used in the future, the dose is 30 to 60 mg, and at this dose, in fact, the QTc prolongation rates are very low, just 3% to 4%. This is very similar to what we see with other drugs—IDH inhibitors etc.
Clinically, we have never seen any major cardiac events, in our experience, with quizartinib as a single agent. There has been 1 report of a cardiac event, and this is out of 1100 patients treated on quizartinib, and this could just be because these are older patients. So we don’t think that there’s a clinical cardiac signal, but I would recommend community doctors to monitor the QTc as recommended in the insert and avoid concomitant QT-prolonging meds like antiemetics that can be replaced or antifungals so you don’t run that risk, even though it appears to be very small.
Transcript Edited for Clarity