ASH 2023 | QuANTUM-First: FLT3-ITD-specific MRD to assess benefits of quizartinib in FLT3-ITD+ AML

The QuANTUM-First trial is the pivotal trial of quizartinib. It led to the drug approval this past year. It’s a Phase III study that enrolled newly diagnosed patients with FLT3-ITD-positive AML who were fit for intensive induction chemotherapy, and used that as a backbone of seven and three induction and high dose ara-C consolidation, to which a 14 day course of either quizartinib, a FLT3 inhibitor or placebo, was added for 14 days on each of the intensive chemotherapy cycles, and this was followed by up to three years of maintenance therapy with, again, what the patients were assigned to at randomization, and patients could go off study for transplant at any time once they were found to be in remission. 

So the basic design of the study is that and what we found from the study was that significant improvement in overall survival was seen in the quizartinib arm, but despite that, the remission rates were very similar. And so a question that arises is why? If you’re seeing similar response rates, why do you get better survival? And it could be a bunch of different things. But one thing we thought reasonably could be inferred was perhaps the patients treated with quizartinib got qualitatively better remissions, deeper remissions, and perhaps either more MRD-negative remissions or a deeper level of MRD. So we had actually expected that we’d want to ask this question and pre-specified analysis of MRD, using a FLT3-ITD quantitation, prior to the study. And what I’m presenting here at the ASH meeting are results from that study. 

We presented kind of preliminary data last year looking at patients post-induction, but this year we’ll be looking at post-induction, post two cycles of chemotherapy, which is a standard place to look at MRD, and then also patients who completed consolidation, so prior to the maintenance phase. What we found was that, not surprisingly, there was a deeper level of MRD in the quizartinib arm than in the placebo arm, as well as more patients that were undetectable at each of these time points. And then lastly, I should mention, the assay that was used is very similar to what’s been used in other settings to measure the depth of FLT3-ITD allele burden. And this uses an ultra sensitive test that PCRs up the juxtamembrane region in FLT3 where these ITD mutations occur, and then sequences the products. This has been used with chemotherapy and shown that patients who are MRD-positive by this assay have higher relapse rates and worse survivals, and also in terms of guiding maintenance therapy, there was recently a presentation at the EHA meeting using gilteritinib and showing that MRD was a strong predictor of the benefit of gilteritinib in that setting. We, again, saw that patients who were MRD-positive really benefited from quizartinib and had superior survival to the placebo arm, though interestingly, patients who had undetectable MRD did similarly well in each treatment arm, there were just more of those patients treated with quizartinib.