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Quizartinib Data Move FLT3 Inhibition Forward in AML Paradigm

Gina Columbus @ginacolumbusonc
Published: Tuesday, Mar 19, 2019

FLT3 inhibition continues to be explored as a therapeutic option for patients with FLT3-mutant acute myeloid leukemia (AML), with quizartinib at the forefront following intriguing results of the phase III QuANTUM-R trial, experts discussed during an OncLive® Peer Exchange®.

FLT3 is expressed in approximately 30% of all patients with AML,1 leading to an area of active investigation. It has been determined that FLT3 mutations can be divided into internal tandem duplications (FLT3-ITD) in or near the juxtamembrane domain of the receptor, or as point mutations that lead to single amino acid substitutions that occur in the activation loop of the tyrosine kinase domain (FLT3-TKD).

The first of the FLT3 inhibitor regulatory approval stream began with the FDA approval of midostaurin (Rydapt) for the treatment of adult patients with newly diagnosed FLT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. The FLT3 inhibitor was approved along with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay, to test for FLT3 mutations in patients with AML.

Other type I inhibitors that have been evaluated in patients with FLT3-mutant AML include lestaurtinib, sunitinib (Sutent), crenolanib, and gilteritinib (Xospata), which was approved by the FDA in November 2018 as a therapy for adult patients with FLT3 mutation–positive relapsed or refractory disease.

The gilteritinib approval was based on findings from the ADMIRAL trial, in which 138 adult patients with FLT3-positive relapsed/refractory AML received the FLT3 inhibitor orally at 120 mg daily. At a median follow-up of 4.6 months, the rate of complete remission (CR) or CR with partial hematologic recovery was 21% (n = 29; 95% CI, 14.5-28.8).2

Type II inhibitors that have been evaluated in this space include sorafenib (Nexavar), ponatinib (Iclusig), and quizartinib. The FDA granted a priority review designation to a new drug application (NDA) for quizartinib in November 2018 for the treatment of adult patients with relapsed/refractory FLT3-ITD–positive AML. Under the Prescription Drug User Fee Act, the FDA will decide on the NDA by May 25, 2019.

The designation is based on findings from the pivotal phase III QuANTUM-R trial, which explored quizartinib compared with salvage chemotherapy in patients with FLT3-ITD–positive relapsed/refractory AML following frontline treatment with or without hematopoietic stem cell transplantation (HSCT). Updated data from the study presented at the 2018 American Society of Hematology Annual Meeting showed that the overall survival (OS) benefit with quizartinib in this population was reported across patient subgroups and reproduced consistently across sensitivity analyses.3

In the open-label QuANTUM-R study, patients with FLT3-ITD–positive relapsed/refractory AML were randomized in a 2:1 ratio to receive once-daily quizartinib at 60 mg, with a 30-mg lead-in (n = 245) or investigators’ choice of salvage chemotherapy that was selected by physicians prior to randomization. Chemotherapy regimens included low-dose cytarabine (n = 29); the combination of mitoxantrone, etoposide, and cytarabine (MEC; n = 40); or the combination of fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin (FLAG-IDA; n = 53).

Baseline patient characteristics were well balanced across the treatment arms. The median patient age in the quizartinib arm was 55 years (range, 19-81), and 89% had an ECOG performance status of 0 or 1. Additionally, 33% of patients were refractory to prior therapy, 23% had relapsed after remission with HSCT, and 45% had relapsed after remission without HSCT.

Also, among patients receiving quizartinib, the FLT3-ITD variant allele frequency ranges included <3% (1%); ≥3% to ≤25% (27%); >25% to ≤50% (35%); and >50% (37%). Cytogenetic risk status included favorable (5%), intermediate (78%), unfavorable (9%), and unknown (8%).

Results showed that, at a median follow-up of 23.5 months, the median OS was 6.2 months (95% CI, 5.3-7.2) with quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177). Earlier reported data from QuANTUM-R showed that quizartinib had led to a 24% reduction in the risk of death versus salvage chemotherapy.

This OS benefit was upheld across 3 prespecified sensitivity analyses. In the first, which censored for the effect of transplant, the median OS with quizartinib versus salvage chemotherapy was 5.7 months versus 4.6 months (HR, 0.79; 95% CI, 0.59-1.05; P = 0.519). An analysis censoring for the use of other FLT3 inhibitors showed a median OS of 6.6 versus 5.0 months, respectively (HR, 0.74; 95% CI, 0.55-0.99; P = .0203).

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