Quizartinib May Represent an Additional Therapeutic Option for FLT3-ITD+ AML

Quizartinib produced an overall survival (OS) benefit when compared with placebo in patients with FLT3-ITD–positive acute myeloid leukemia (AML), positioning it as an acceptable potential treatment option in this population, according to Mark Levis, MD, PhD. He added that, if approved by the FDA, minimal residual disease (MRD) levels may help predict which patients will derive the most benefit from treatment with this agent.

On October 24, 2022, the FDA granted priority review to the new drug application for quizartinib, a selective FLT3 inhibitor, plus cytarabine and anthracycline induction and cytarabine consolidation in adult patients with newly diagnosed FLT3-ITD–positive AML. The FDA is expected to decide on the application by April 24, 2023.

This approval would be supported by findings from the phase 3 QuANTUM-First trial (NCT02668653), in which patients who received quizartinib in combination with cytarabine/anthracycline induction and cytarabine consolidation and as monotherapy following consolidation had a median OS of 31.9 months (95% CI, 21.0-not estimable) vs 15.1 months (95% CI, 13.2-26.2) in those in the placebo arm.¹

Previously, midostaurin (Rydapt), another FLT3 inhibitor, was approved by the FDA in combination with chemotherapy for adult patients with newly diagnosed FLT3-positive AML, becoming the standard of care in this population. In the pivotal phase 3 RATIFY trial (NCT00651261), treatment with midostaurin plus standard chemotherapy led to a median OS of 74.7 months (95% CI, 31.5-not reached) vs 25.6 months (95% CI, 18.6-42.9) with chemotherapy alone (HR, 0.78; 95% CI, 0.63-0.96; P = .009). Common adverse effects (AEs) with midostaurin included thrombocytopenia, neutropenia, anemia, febrile neutropenia, and infection.²

“On the surface, there’s a good justification to start using quizartinib for patients with newly diagnosed FLT3-ITD–positive AML,” Levis said.

In an interview with OncLive^®, Levis discussed potential changes to the FLT3-ITD-mutated AML treatment landscape that may occur if the FDA approves quizartinib, key efficacy and safety data with the agent, and how quizartinib compares with midostaurin.

Levis is the program leader of the Hematologic Malignancies and Bone Marrow Transplant Program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

OncLive: How might the FDA approval of quizartinib in newly diagnosed, FLT3-positive AML affirm or change current practice patterns?

Levis: Quizartinib has been studied both in the up-front setting and in the relapsed setting. Despite the FDA’s objections to the design of the phase 3 relapsed/refractory [QuANTUM-R] trial [NCT02039726], it was positive. Arguably, the [QuANTUM-R] randomized data support the use of quizartinib in any circumstances, [including] relapsed and newly diagnosed, for patients with FLT3-ITD–positive AML. However, the FDA label [may not] say that; [it may say] up front only.

[If approved], we [would] have the choice [between] quizartinib and midostaurin. We’re comfortable with midostaurin. It’s on our formulary, it works well, and we don’t have many objections to it. [However, 1] objection is when the patient smells the pill, they don’t like it as much. The midostaurin pills smell bad, and they’re often not well tolerated, although with chemotherapy, they are reasonably [tolerable]. Providers now have a comfort level and experience with that drug.

Quizartinib is considered a more potent FLT3 inhibitor and is specific for the FLT3-ITD mutation, which is the scarier mutation. In theory, [we would] want to use a better drug. QuANTUM-First used quizartinib in patients of many ages, which was not the case with midostaurin, so we have justification to use [quizartinib] in patients of any age. The QuANTUM-First trial [also included] a more challenging patient population, [those of all ages with] FLT3-ITD mutations, as opposed to [the RATIFY trial, which included patients with] FLT3-TKD mutations [who were] under the age of 60. Looking at the outcomes, although it’s always perilous comparing 2 trials of different eras, the data in QuANTUM-First look more compelling.

What are some of the key differences between quizartinib and midostaurin?

[Quizartinib] is FLT3 inhibitor specific for wild-type FLT3 and the FLT3-ITD mutation. It has little activity against FLT3 with a TKD mutation, or a gatekeeper mutation. That represents a source of resistance. That’s the less common version of FLT3 mutations and is much less impactful from a prognosis standpoint.

The dilemma facing clinicians, when they have a patient with a FLT3-ITD mutation, will be: Should we use a drug that is designed specifically as a FLT3 inhibitor to more effectively inhibit the kinase activity of the mutation that’s clearly driving this disease? Midostaurin is more of a partial inhibitor. It’s less potent, less effective, and probably less tolerable. There will be an impetus to take advantage of the selective mechanism of action of quizartinib.

However, [because] quizartinib is a more potent FLT3 inhibitor and has activity against the c-Kit receptor, as does midostaurin, it will be more myelosuppressive than midostaurin. Finally, quizartinib has a long half-life. You don’t get to [simply stop the drug when a patient has] myelosuppression. You’re not going to stop the drug quickly because it hangs around for 2 weeks. [The treatment decision] isn’t clear cut, but there’s good reason to switch over to quizartinib.

What key efficacy data with quizartinib were seen in QuANTUM-First?

The primary end point of OS is the key efficacy end point [of the trial]. The tricky [aspect of] complete remission is how you define the remission and when [a patient] achieves the remission. That’s all over the map. Should [a patient] achieve it in 42 days, 60 days, etc.? Those are parameters measured in [end points] like event-free survival. An event is failure to achieve a remission, relapse, or death. If we use those metrics, quizartinib doesn’t look [favorable], because it sometimes might take longer to achieve remission because of the myelosuppressive effects.

The more important end point is: Is my patient living longer? That’s the key. [Quizartinib] has an OS benefit, which is what the FDA is looking at, what they asked for, and arguably the most important metric.

In addition, quizartinib is well tolerated. No [concerning] safety signals came out [of the trial]. Patients [often] don’t know when they’re taking the drug; you can’t tell it from placebo easily. [Many findings from QuANTUM-First] favor [it’s use]. However, the key metric from that study, the one that counts, is survival.

What would be the importance of monitoring patients for myelosuppression when they receive quizartinib, and what other AEs are important to note with this agent?

[Although] the FDA is [worried] about QT prolongation, [many] clinicians who manage leukemia [do not put much clinical emphasis on] QT prolongation. That is a main toxicity of quizartinib, supposedly, although it was hardly noticeable in the QuANTUM-First trial because it was carefully monitored. [The investigators] did electrocardiograms, and they were careful to avoid certain drug interactions.

Another primary toxicity [of quizartinib] is myelosuppression. There was an increased rate of death in patients on the quizartinib arm, almost certainly from infection. Looking at the survival curves, the quizartinib arm dropped quicker initially, during the first month or so, and then it quickly crossed over, recovered, and was clearly better than the control arm. That’s almost certainly a reflection of that myelosuppression.

This will be important when clinicians try to treat the myelosuppression with antibiotics. [If we want to] give patients posaconazole or voriconazole, a mold-active azole, [we should] be careful with those because they will prolong the half-life and effect of quizartinib and potentially cause more myelosuppression. The toxicity is focused entirely around how myelosuppressive the agent is, and the minor component of QT prolongation.

What did this trial reveal about the predictive value of MRD in the FLT3-ITD–mutated AML population?

The QuANTUM-First trial was the first trial that prospectively used a marker for MRD for the FLT3-ITD mutation. The data were limited because of how heterogeneous the population was. Some [patients] would go to transplant, some would get consolidation, and some would leave the study, so we didn’t have uniform time points to look at the MRD assay.

However, the MRD assay predicted for improved OS. [If a patient] had a higher level of MRD, [they were] less likely to survive. If they had a lower level of MRD going into transplant, they may not have needed the drug after transplant, or the drug had much less of an effect after transplant.

The other component of that trial is that after allogeneic transplant, patients were allowed to continue the drug. This is a disease where patients are routinely taken to transplant, so this sets the framework for the use of the drug throughout the patient’s treatment, [including] induction, consolidation, and post-transplant maintenance.

What additional research with FLT3 inhibitors is informing the AML treatment paradigm?

A related drug, gilteritinib [Xospata], was tested in a randomized phase 3 study in the post-transplant setting. In that trial, [gilteritinib] did not reach its primary end point of relapse-free survival after transplant. When patients worldwide were taken to allogeneic transplant and then randomized to get gilteritinib, a good FLT3 inhibitor, or placebo, the benefit [with gilteritinib] did not reach statistical significance.

That will have implications regarding how we interpret patients on the QuANTUM-First trial who were taken to allogeneic transplant. Was there a need to get the drug post-transplant? The story is much more complex, MRD plays a role, and the myelosuppression probably plays a role, as both [quizartinib and gilteritinib] have long half-lives and are myelosuppressive.

References

1. Quizartinib with standard of care chemotherapy and as continuation therapy in patients with newly diagnosed FLT3-ITD (+) acute myeloid leukemia (AML) (QuANTUM-First). ClinicalTrials.com. Updated December 29, 2022. Accessed March 20, 2023. https://clinicaltrials.gov/ct2/show/NCT02668653
2. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359