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
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.
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
Figure. Quizartinib in Adult Patients With Relapsed/Refractory AML2
“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.