Quizartinib Plus Chemotherapy Improves EFS, RFS in Newly Diagnosed FLT3-ITD–Negative AML

Pau Montesinos, MD, PhD

The combination of quizartinib plus standard induction and consolidation 3+7 chemotherapy, followed by quizartinib maintenance, led to improvements in event-free survival (EFS) and relapse-free survival (RFS), and the regimen generated a trend toward prolonged overall survival (OS) vs chemotherapy plus placebo in adult patients with newly diagnosed FLT3-ITD–negative acute myeloid leukemia (AML), according to preliminary data from the phase 2 QUIWI trial (NCT04107727).

Findings presented at the 2023 EHA Congress showed that patients in the quizartinib arm (n = 180) experienced a median EFS of 16.5 months vs 10.6 months for the placebo arm (HR, 0.741; 95% CI, 0.535-1.026; P = .059). In patients who achieved a complete remission (CR) or CR with incomplete neutrophil or platelet recovery after 1 or 2 induction cycles, the quizartinib regimen (n = 131) produced a median RFS that was not reached (NR) vs 18.6 months for the placebo regimen (n = 70; HR, 0.631; 95% CI, 0.414-0.962; P = .031).

The median OS was NR in all patients in the quizartinib group vs 20.2 months for the placebo group (HR, 0.569; 95% CI, 0.385-0.841; P = .004).

“Our data might show that there is a way of offering targeted therapy in combination with 3+7 [chemotherapy] to improve long-term outcomes in incurable patients through quizartinib,” lead study author, Pau Montesinos, MD, PhD, said in an interview with OncLive^®.

In the interview, Montesinos, an attending physician and hematologist at the University Hospital La Fe in Valencia, Spain, discussed the preliminary results of the QUIWI trial, expanded on the potential implications for the use of quizartinib plus chemotherapy in newly diagnosed patients with FLT3-ITD–negative AML, and detailed the next steps for this study and future research.

OncLive: What was the rationale of investigating the combination of quizartinib and chemotherapy in patients with FLT3-ITD–negative AML?

Montesinos: The rationale to conduct this clinical trial was based on preliminary clinical results [from the phase 2 SORAML trial (NCT00893373) of sorafenib (Nexavar) plus chemotherapy], which elicited responses in patients with relapsed/refractory AML without FLT3-ITD mutations. When given as a single, oral agent, this agent showed remarkable efficacy in patients with [FLT3-ITD] wild-type disease.

The mechanism of action of [quizartinib], which is a potent and selective FLT3 type II inhibitor, inhibits the FLT3 receptor on its inactive form. We know that FLT3 plays an important role in hematopoiesis. The ligand factor activates under normal conditions, activating phosphorylation and downstream signal transduction. Therefore, there is a rationale that inhibiting this receptor could be useful, at least to inhibit the proliferation and inhibit the survival mechanisms in leukemic cells, irrespectively of the presence of a constitutive FLT3 activation through TKD or ITD.

Could you provide an overview of the patients who were included in QUIWI? What methods were utilized in this study?

This was a phase 2, 2:1 randomized trial, with quizartinib or placebo [added to chemotherapy]. The backbone schedule for all patients was a 3+7 chemotherapy at standard doses, including 12 mg/m² of idarubicin and 200 mg/m2 of cytarabine.

These were fit patients. All were between 18 and 70 years [of age], and the study ran between 2019 to 2021, so this was a [COVID-19] pandemic trial.

We were able to screen [493] patients. Of these, [273] patients were randomly assigned to placebo or quizartinib. The inclusion/exclusion criteria allowed the vast majority of fit patients to enroll. There were some specific exclusion criteria regarding the QTc interval prior to randomization. Additionally, patients with secondary AML were eligible.

[This study required] patients to have FLT3-ITD non-mutated [AML]. There was central screening, and patients with a FLT3-ITD ratio more than 0.03 were not allowed. All other genetic subtypes were allowed to be included.

Could you expand on the key efficacy findings presented at the 2023 EHA Congress?

This was a preliminary analysis. The definitive analysis of the trial will be performed by the end of 2023 because we will require more observation of patients, as per protocol. However, in this preliminary analysis, the key findings were that OS was improved. OS at 3 years was approximately 40% in the placebo arm and 60% in the in the experimental arm. This was coupled with a significant improvement RFS. With a P value of 0.059, there is a trend toward improvement on EFS.

The CR rate was similar between both arms at 78% [for each group] after 1 or 2 cycles of induction. Additionally, the CR with minimal residual disease negativity rate, which was performed centrally, was similar between both arms at 44% [for quizartinib] vs 43% [for placebo].

What was found regarding safety in the preliminary analysis?

These were all preliminary data, and we cannot draw any valid conclusion until we have a final analysis. We did a first approach on toxicity, finding that there was more grade 1 QT prolongation with quizartinib compared with placebo. However, there were not [increased instances of] grade 2 or 3 cardiac events with quizartinib vs placebo, so this was reassuring. We found that for febrile neutropenia, [other] hematologic events, and infections, there were not sizable or remarkable differences between both arms.

In general, our data support [safety] findings from the [phase 3] QuANTUM-First trial [NCT02668653] that quizartinib [plus chemotherapy is quite manageable. Of course, we [may] need dose adjustments with quizartinib. Of note, the dose [of quizartinib in QUIWI] was 60 mg per day, not 40 mg that was used in patients with FLT3-ITD–mutated AML [in QuANTUM-First].

We gave 30 mg instead of 60 mg when a patient was taking a potent CYP3A inhibitor. There was monitoring of QT, and we needed to balance electrolytes in placebo and the experimental arm. With this management, we are not harming patients [with the addition of quizartinib]. That was the first objective: to [ensure the combination was] safe with patients.

What are the next steps for this study and future research for quizartinib in patients with FLT3-ITD–negative AML?

This was a phase 2 trial, not a phase 3 trial. If these preliminary results are confirmed, we will need a confirmatory study. The question is how to do this confirmatory study. [It could potentially be] in a randomized manner again, if we can justify doing a new randomized trial if we have these [efficacy] differences confirmed. Some kind of confirmatory data will be needed or advisable. Also, it is important that we have a biomarker plan. This is very necessary to understand how the combination is working. We have a good rationale, but we need to demonstrate this rationale.

Regarding targeted therapies in AML, this may open a new targeted therapy for up to 80% of patients who are FLT3-ITD–negative. It could be useful in the future. There are also some investigations to do on which patients are benefiting more from the addition of quizartinib, and we have some preliminary data from a sensitivity analysis showing that high-risk patients are not benefiting from the addition of quizartinib. But low- or intermediate-risk patients do benefit. We need some strategies to better select high-risk patients in a timely manner [who could benefit from treatment with] quizartinib.

We need to look at the future, if these data are confirmed. What could be the place [for quizartinib] in the current landscape where other young patients who are treated with curative intention with 3+7 chemotherapy? There are now several trials investigating 3+7 plus IDH inhibitors. Additionally, 3+7 plus menin inhibitors could also be explored.

Reference

Montesinos P, Rodríguez-Veiga R, Bergua Burgues JM, et al. Preliminary results of QUIWI: a double blinded, randomized clinical trial comparing standard chemotherapy plus quizartinib versus placebo in adult patients with newly diagnosed flt3-itd wild-type AML. Presented at: 2023 European Hematologic Association Congress; June 8-15, 2023; Frankfurt, Germany. Abstract S130.