QuANTUM-Wild Trial to Explore Correlative Outcomes With Quizartinib in FLT3-Negative AML

David M. Swoboda, MD

Since the FLT3 inhibitor quizartinib (Vanflyta) has shown efficacy in both patients with FLT3-ITD–positive acute myeloid leukemia (AML) and those with FLT3-ITD–negative AML, ongoing research aims to answer questions regarding this agent’s mechanism of action and the predictive value of FLT3 gene expression, according to David M. Swoboda, MD.

In 2023, the FDA approved quizartinib in combination with standard induction and consolidation chemotherapy, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed, FLT3-ITD–positive AML.1 In the pivotal phase 3 QuANTUM-First trial (NCT02668653), patients who received quizartinib plus chemotherapy (n = 268) achieved a statistically significant overall survival (OS) improvement vs those who received placebo plus chemotherapy (n = 271; HR, 0.78; 95% CI, 0.62-0.98; 2-sided P = .0324).

The phase 2 QUIWI trial (NCT04107727) showed the efficacy of quizartinib in patients with FLT3-ITD–negative AML.2 At a median follow-up of 39.4 months, the median event-free survival (EFS) was 18.8 months with quizartinib plus induction and consolidation chemotherapy (n = 180) vs 9.9 months with placebo plus chemotherapy (n = 93; HR, 0.732; 95% CI, 0.533-1.005; P = .0455). The median OS was not reached vs 29.3 months in the quizartinib and placebo arms, respectively (HR, 0.625; 95% CI, 0.436-0.897; P = .0009).

Based on the positive findings from QUIWI, the ongoing, confirmatory, phase 3 QuANTUM-Wild trial (NCT06578247) is evaluating quizartinib plus chemotherapy vs placebo plus chemotherapy in patients with newly diagnosed, FLT3-ITD–negative AML.3 OS will serve as the primary end point. Key secondary end points will include EFS, duration of response, recurrence-free survival, complete response (CR) rate, rate of CR with minimal residual disease, and safety.

“We have to understand what specific mutations occur [in each patient] to better understand their prognosis and give them the best treatment options possible,” Swoboda said in an interview with OncLive®.

In the interview, Swoboda discussed the evolution of FLT3-targeted therapies for patients with FLT3-positive AML, data with quizartinib in patients with FLT3-negative AML stemming from the QUIWI trial, and how the QUIWI findings provided the rationale for the QuANTUM-Wild trial.

Swoboda is a hematologist oncologist at Tampa General Hospital (TGH) and clinical director of Leukemia at TGH Cancer Institute in Florida.

OncLive: What is the importance of distinguishing between the FLT3-TKD and FLT3-ITD phenotypes of AML?

Swoboda: We now use [somatic] genetic testing to understand how best to diagnose a patient [with AML], put them in a prognostic category, and treat them. [This is] not genetic testing that [assesses genetics that are] passed down from one generation to another. [I am referring to testing for] mutations that people acquire—generally as they age—that ultimately lead to [the development of] this disease.

FLT3 mutations, which are one of the most common mutations in AML, [are found in approximately] 30% of patients. There are 2 different [types of] FLT3 mutation: FLT3-ITD mutations and FLT3-TKD mutations. They are vastly different [from each other]. Patients with FLT3-ITD–mutated disease tend to have more aggressive disease compared with those with FLT3-TKD mutations, and they respond differently to different therapies.

Therapeutic intervention [for patients with AML] has changed and is [now] molecularly based and targeted. We have established different drugs, some of which target FLT3 and some of which target other gene mutations, like IDH1/2. Some of those drugs that target FLT3 target both the ITD and TKD mutations, whereas others target the ITD mutations alone.

Quizartinib—one of the newest FDA-approved drugs [for patients with AML]—was approved based on the QuANTUM-First data. [This agent] specifically targets FLT3-ITD–positive disease, whereas gilteritinib [Xospata]—a drug that was approved based on the phase 3 ADMIRAL study [NCT02421939] in relapsed/refractory AML—can be used in both FLT3-ITD– and -TKD–positive disease. Midostaurin [Rydapt], which was the [first] drug approved for [patients with FLT3-positive AML], also works in FLT3-ITD– and -TKD–positive disease.

What was the rationale for the QUIWI study investigating quizartinib in patients with FLT3-ITD–negative AML?

We [have historically thought we could design] targeted therapies to specifically target a mutation, and then we could design trials to focus on that mutational subgroup. The story for the FLT3 inhibitor quizartinib was that most clinical trials have to—at least initially as proof of concept—include both patients with mutations, as well as those with wild-type disease, because we want to understand: Does a drug work in patients with mutations? Does it not work in patients who lack a particular mutation.

Similar to most targetable agents, we found that quizartinib worked well in patients with FLT3 mutations, so we expanded that cohort into a large, randomized phase 3 clinical trial of 7+3 chemotherapy plus quizartinib vs standard-of-care [SOC] induction with 7+3 chemotherapy [alone]. We found that patients with FLT3-ITD–mutant AML had better overall outcomes if they received quizartinib in combination with SOC [vs SOC alone]. Interestingly, we realized that FLT3-negative—or wild-type—patients also seemed to initially have better outcomes with this drug [than with SOC alone].

We spent additional time and research investigating that wild-type cohort. Why are those patients responding to therapy that's targeting a mutation they lack? Ultimately, we wanted to see whether [quizartinib] could improve treatment efficacy for patients [with FLT3-negative disease]. Therefore, we launched the QUIWI study, which is a randomized phase 2 clinical trial. It was similar to QuANTUM-First, but we enrolled patients with FLT3-ITD–negative [disease]. We found that, similarly to in the FLT3-ITD–mutant subset of patients, the addition of quizartinib to SOC chemotherapy led to improved OS in patients with FLT3-negative disease.

What questions did the QUIWI trial findings raise about the mechanism of action of quizartinib?

When we launch a study, we [typically] enroll a broad population of patients with AML, and then eventually take [the investigational agent] down its path [toward] approval. However, rarely do we go back and [evaluate the agent's efficacy] outside that approval [indication], [especially with an agent] that is supposed to be selective for a particular mutation. [The QUIWI findings made us ask]: What is the mechanism of action [of quizartinib]? Why, in FLT3-negative patients, were we seeing better and more durable responses [vs SOC chemotherapy alone]? Why was this occurring when we originally thought and still do feel like quizartinib is primarily a FLT3-targeting agent?

[The expansion of this research] has led to a better understanding that not all patients who lack [a FLT3] mutation are created equal. That's where gene expression—specifically expression of FLT3—[becomes relevant]. We found through correlative analysis that [some] patients with FLT3-negative disease ultimately have [FLT3] expression levels similar to those we see in patients with FLT3-positive disease. Patients don't necessarily have to have a FLT3 mutation to respond to a FLT3-targeted therapy.

How might the efficacy of quizartinib in patients with FLT3-negative AML affect genetic testing practices and the clinical use of this agent?

The QUIWI study led by the PETHEMA Foundation was a larger proof-of-concept trial has now led to the global, randomized [QuANTUM-Wild] clinical trial. Can we [replicate the QUIWI trial findings] in a large, international study [that is also comparing] SOC plus quizartinib vs SOC alone? Interestingly, at least in most clinics—even academic clinics—we do not necessarily look at FLT3 expression. A lot of times, we also do not necessarily use what is considered the best test for FLT3 testing. Sometimes we even miss patients with FLT3-positive disease if we don't use the appropriate test, which is not necessarily large-panel sequencing, but a lot of times is polymerase chain reaction–based testing specifically for that FLT3 mutation.

Most patients with FLT3-positive disease should probably receive a FLT3 inhibitor. That [decision] is easy. Then, [we need to] tease out which patients within the non-mutant group would benefit most from a FLT3 inhibitor vs potentially a non-FLT3–targeted therapeutic option [or combination] we're trying to develop [for patients with] multiple mutations. [In the future, we may] better understand gene expression and which FLT3-negative patients are most likely to respond to FLT3 inhibitors. Then, we may ultimately prefer initially giving those patients FLT3-targeted therapy.

What makes the QuANTUM-Wild trial objectives unique compared with typical clinical trials in AML?

The [sponsoring] company is interested in doing large-scale correlative analyses to figure out which patients are most likely to respond to [FLT3-targeted] therapies. [I and the other] investigators on the QuANTUM-Wild study are focused on the research aspect of the trial. [This is] not a normal, large phase 3 clinical trial where we're only using SOC [in the control arm] and are not heavily invested in the correlative side of things. The correlative analysis is important [for this trial] so we can have a large, strong dataset to answer some of these more challenging questions when this trial is done.

References

1. FDA approves quizartinib for newly diagnosed acute myeloid leukemia. FDA. July 20, 2023. Accessed March 17, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia
2. Final results of Quiwi: a double blinded, randomized Pethema trial comparing standard chemotherapy plus quizartinib versus placebo in adult patients with newly diagnosed FLT3-ITD negative AML. Blood. 2024;144(suppl 1):1512. doi:10.1182/blood-2024-204770
3. Quizartinib or placebo plus chemotherapy in newly diagnosed patients with FLT3-ITD negative AML (QuANTUM-WILD). ClinicalTrials.gov. Updated February 19, 2025. Accessed March 18, 2025. https://clinicaltrials.gov/study/NCT06578247