Oncology Live®
Vol. 20/No. 8
Volume 20
Issue 8

Quizartinib Poised to Expand FLT3 Inhibition Options in AML

Quizartinib, a novel small molecule FLT3 inhibitor, is moving through the pipeline of new drugs under development for patients with FLT3-mutated acute myeloid leukemia, part of a menu of targeted treatment options that is expanding as investigators learn more about the molecular heterogeneity of the disease.

Jorge E. Cortes, MD

Jorge E. Cortes, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Jorge E. Cortes, MD

Quizartinib, a novel small molecule FLT3 inhibitor, is moving through the pipeline of new drugs under development for patients with FLT3-mutated acute myeloid leukemia (AML), part of a menu of targeted treatment options that is expanding as investigators learn more about the molecular heterogeneity of the disease.

FLT3 mutations are expressed in approximately 30% of patients with AML, mostly within the internal tandem duplication (ITD), making the alterations among the most common molecular aberrations identified in the malignancy. Quizartinib specifically targets AML with FLT3-ITD mutations, which are associated with early relapse and a poor prognosis.1

In November 2018, the FDA granted a priority review designation to a new drug application (NDA) for quizartinib for adult patients with relapsed/ refractory FLT3-ITD—positive AML. In April 2019, the FDA added 3 months to the review period for quizartinib to review more data, extending the deadline for a decision on the NDA to August 25, 2019. To date, the FDA has approved 2 drugs that inhibit FLT3 and other kinases in patients with AML: midostaurin (Rydapt) and gilteritinib (Xospata).

The NDA for quizartinib is based on findings from the phase III QuANTUM-R trial (NCT02039726) that demonstrated prolonged overall survival (OS) compared with salvage chemotherapy, according to data presented at the 2018 American Society of Hematology Annual Meeting.2

At a median follow-up of 23.5 months, patients treated with quizartinib had a median OS of 6.2 months (95% CI, 5.3-7.2) compared with 4.7 months (95% CI, 4.0-5.5) for those who received salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).

The study randomized patients 2:1 to receive quizartinib (n = 245) as a monotherapy or physician’s choice of chemotherapy (n = 122). Salvage chemotherapy options were low-dose cytarabine; the combination of mitoxantrone, etoposide, and intermediate-dose cytarabine; and a regimen of fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin.

Figure. Quizartinib in Adult Patients With Relapsed/Refractory AML2

To be eligible for inclusion, patients had to be in first relapse (with duration of remission ≤6 months) or refractory after prior therapy, with or without hematopoietic stem cell transplantation. Participants had to have presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood. The primary endpoint was OS, and the secondary endpoint was event-free survival (Figure).2 “The results of the QuANTUM-R trial showed an improvement in survival. The hazard ratio was 0.76, essentially meaning an approximately 24% reduction in the risk of death during the observation period of the study,” said Jorge E. Cortes, MD, in an interview with OncologyLive®.

“This, of course, came with an improvement in the response rate for patients treated with quizartinib. We looked at the composite complete remission [CRc] and CRc with incomplete hematologic recovery,” added Cortes, the principal investigator on the QuANTUM-R trial and the deputy chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Overall, when we put them together, around 60% of patients responded in some way. This is much better than the chemotherapy arm.”

The CRc rate was 48% in those who received quizartinib compared with 27% in those who were given salvage chemotherapy; the overall response rate, comprised of CRc and partial responses, was 69% with quizartinib versus 30% with chemotherapy.

Further, the median event-free survival rate was 1.4 months (95% CI, 0.0-1.9) with quizartinib versus 0.9 months (95% CI, 0.4-1.3) with chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; P = .1071). The median time to first CRc was comparable in both groups: 4.9 weeks (range, 3.7-19.7) with quizartinib versus 4.0 weeks (range 2.0-14.9) with salvage chemotherapy. However, results showed that patients in the quizartinib arm had a median duration of CRc of 12.1 weeks (95% CI, 10.4-27.1) versus 5.0 weeks (95% CI, 3.3-12.6) for those in the salvage chemotherapy arm.

Treatment was well tolerated, with low incidence of grade 3 (4%) and no grade 4 QT prolongation. Two patients in the quizartinib arm discontinued treatment because of QT prolongation. “The concern about QT prolongation, which had been the main dose-limiting toxicity in the phase I study, is [that it is] at a very low rate and really not associated with serious arrhythmias or any other problems,” said Cortes.

Regarding other safety signals, the most common all-grade treatment-emergent adverse events in the quizartinib arm compared with the chemotherapy cohort, respectively, were sepsis or septic shock (22% vs 27%), peripheral edema (21% vs 23%), and constipation (20% vs 23%). “This was a very well-tolerated, oral, outpatient therapy that beats intensive, aggressive chemotherapy where patients would spend a lot of time in the hospital,” added Cortes.

Investigators are further evaluating the efficacy of quizartinib in the first-line setting in the ongoing QuANTUM-First trial (NCT02668653), randomizing patients with FLT3-mutant AML to the FLT3 inhibitor or placebo.

“In the long term, combination therapy will likely be...quizartinib and other drugs, but initially, it will be as a single agent in the salvage setting after resistance or relapse after initial therapy,” Cortes concluded.


  1. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.
  2. Cortes JE, Khaled SK, Martinelli G. Efficacy and safety of single-agent quizartinib (Q), a potent and selective FLT3 inhibitor (FLT3i), in patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)—mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) enrolled in the global, phase 3, randomized controlled Quantum-R Trial. Presented at: 2018 ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract 563.
  3. (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive. Updated February 12, 2019. Accessed April 3, 2019.
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