EHA 2025 | The Phase III QuANTUM-Wild trial: quizartinib in newly diagnosed FLT3-ITD-negative AML

Well, the QuANTUM-Wild trial has been informed and started because of the work of Pau Montesinos and his colleagues in the PETHEMA, a group of clinical investigators in Spain and Portugal. We have known for a very long time that quizartinib has in vitro activity against wild-type normal FLT3, as we’ve seen in the initial phase one study where we had a small group of patients in the dose escalation who did not have a FLT3 mutation. We’ve gone back and checked those by a very sensitive MRD assay. They truly didn’t have a FLT3 ITD, and yet we saw responses. And so we know that this drug binds to the inactive confirmation of FLT3, and so may prevent activation of FLT3 by the FLT ligand, which often is upregulated in patients receiving intensive chemotherapy. Furthermore, there’s retrospective data showing that the expression level of FLT3 wild-type on AML blasts correlates with outcome. There’s also clinical data to suggest that FLT3 inhibitors with a type 2 inhibitor may actually be beneficial. For example, the SOAR AML study that’s been published by Christoph Röllig and his colleagues, showed that there was a leukemia-free survival in all patients receiving intensive chemotherapy with sorafenib versus placebo. The study was not powered to look specifically at a FLT3 ITD group, but the entire group, there was a leukemia-free survival, not an overall survival. And so based on that, Pau Montesinos launched a trial in patients eligible for intensive chemotherapy up to the age of 70 years old, where patients without a FLT3 ITD, they could have a FLT3 TKD, and about 25% of them did, were treated with seven and three chemotherapy with quizartinib at a slightly higher dose than used in QuANTUM-First, it’s 60 milligrams. I guess that’d be the equivalent of 55 milligrams in the FDA-labeled formulation once daily on days 8 through 21. And they could then get high-dose cytarabine consolidation with quizartinib and continue on maintenance. They could get transplanted at any time. And this was versus a placebo. And what has been presented and soon to be published is that there was an improvement in both overall and event-free survival with the addition of quizartinib in these patients who did not have a FLT3 ITD. What’s interesting about that analysis is when they looked at both younger and older patients, there was a survival benefit. So unlike QuANTUM-First, there was a survival benefit. And the second is they did not see what we saw in QuANTUM-First. They did not see that early drop in survival with quizartinib, especially in the older patients. And I think this really speaks to the importance of looking at the supportive care that patients with AML get. And it’s a distinction between a large global international study like QuANTUM-First and a study done by very learned leukemia investigators who work closely together. They have standardized protocols for supportive care on their AML trials in the PETHEMA group. So I think that’s an important lesson. So age didn’t matter. What did matter in their subset analysis was that there was only a survival benefit as well as a relapse-free survival benefit in patients with either favorable or intermediate risk disease by ELN 2017. In ELN 2017 adverse risk, they did not see a survival benefit. As a corollary of that study, investigators have determined that there is a FLT3-like expression signature found in AML blasts, in patients who, in samples that don’t have a FLT3 ITD. When they then applied that signature to their population, they found that the patients with the FLT3-like expression signature were the ones to have the survival benefit. There was no benefit if they didn’t have that. And interestingly, that expression signature was enriched for patients with NPM1 and DNMT3A mutations. So that’s the foundation of QuANTUM-Wild. We are basically going to replicate that study with patients up to the age of 70, fit for intensive chemotherapy, without a FLT3 ITD, randomized to get standard 7 and 3 with HIDAC with either quizartinib at 60 milligrams daily or with placebo. The primary endpoint of the study is a survival endpoint. We also have an arm C in there, where patients who are initially getting quizartinib during induction placebo will not get it during the maintenance, to give us some, maybe some data at least, on the importance of continuing quizartinib as a maintenance at that point. I’d like to finish with a shout out to Mark Levis, who will be presenting molecular data at this Congress on Sunday, June 15th. He’s presenting molecular data showing that in patients in the QuANTUM-First, who had FLT3 ITD, NPM1, and DNMT3A, there was a significant survival benefit of quizartinib versus placebo, and this was seen also in the older patients. And so instead of being ageist about which patients should get quizartinib if they have a FLT3 mutation or otherwise, and we should be thinking, are they fit for potentially curative intensive chemotherapy regardless of age, especially if they have a genotype that suggests that long-term survival is possible after intensive chemotherapy with quizartinib with or without allogeneic transplant.

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