Quizartinib Receives Japanese Approval in Relapsed/Refractory FLT3+ AML

The Ministry of Health, Labor and Welfare of Japan has approved quizartinib for the treatment of adult patients with relapsed/refractory FTL3-ITD–positive acute myeloid leukemia, as detected by an MHLW-approved assay.

The Ministry of Health, Labor and Welfare (MHLW) of Japan has approved quizartinib (Vanflyta) for the treatment of adult patients with relapsed/refractory FTL3-ITD—positive acute myeloid leukemia (AML), as detected by an MHLW-approved assay.1

The approval of the second-generation FLT3 inhibitor is mostly based on the phase III findings of the QuANTUM-R trial, as well as a phase II study, which demonstrated that oral quizartinib monotherapy showed a statistically significant improvement in overall survival (OS) compared with chemotherapy in this patient population.2

“With the approval of Vanflyta, patients with relapsed/refractory FLT3-ITD AML in Japan will now have access to this important new treatment option that specifically targets the underlying driver of disease, and has a proven survival benefit compared to chemotherapy,” Wataru Takasaki, PhD, corporate officer, head of Oncology Function, and head of R&D Division in Japan, Daiichi Sankyo, the developer of quizartinib, in a press release. “We are proud that Vanflyta is the first of seven new molecular entities we are committed to delivering by 2025 with the goal of transforming science into innovative treatments for patients with cancer.”

In the international, phase III QuANTUM-R trial, investigators evaluated quizartinib compared with chemotherapy in patients with relapsed/refractory FLT3-ITD—mutated AML. Patients were randomized 2:1 to once-daily quizartinib at 60 mg, with a 30-mg lead-in (n = 245) or investigators’ choice of salvage chemotherapy that was selected prior to randomization. Chemotherapy choices included low-dose cytarabine (n = 29); the combination of mitoxantrone, etoposide, and cytarabine, (MEC; n = 40); or the combination of fludarabine, cytarabine and GCSF 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 and ECOG performance status of 0-1. Thirty-three percent of patients were refractory to prior therapy, 23% had relapsed after remission with HSCT, and 45% had relapsed after remission without HSCT.

Results showed that quizartinib led to a 24% reduction in the risk of death compared with chemotherapy (HR, 0.76; 95% CI, 0.58-0.98). The median OS was 6.2 months (95% CI, 5.3-7.2) in patients on the quizartinib arm compared with 4.7 months (4.0-5.5) in those who received salvage chemotherapy.

Moreover, the data that were submitted with the application for approval showed that the median event-free survival (EFS) was 1.4 months (95% CI, 0.0-1.9) with quizartinib compared with 0.9 months (95% CI, 0.4-1.3) with salvage chemotherapy (HR, 0.90; 95% CI, 0.70-1.16; 1-sided, stratified log-rank P = .1071).

Regarding safety, the most common treatment-related adverse events (AEs) in those who received quizartinib were nausea (33.2%), electrocardiogram QT prolonged (24.9%), anemia (24.9%), and thrombocytopenia (21.2%) in the Japanese labeling.

The open-label, single-arm phase II study, in which the quizartinib approval was also partly based on, evaluated quizartinib in Japanese patients with relapsed/ refractory FLT3-ITD AML. The study met its primary endpoint of achieving a pre-determined composite complete remission rate at an interim analysis, which led to the trial ending early. Overall, the efficacy and safety profile of quizartinib that was observed in the phase II trial in Japan appeared to be consistent with that of QuANTUM-R.

In May 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8-3 against approving a new drug application for quizartinib for adult patients with relapsed/refractory FLT3-ITD—positive AML. Prior to the ODAC meeting, the FDA conducted its own efficacy analysis, and found that the median OS with quizartinib was 26.9 weeks (95% CI, 23.1-31) versus 20.4 weeks (95% CI, 17-25.2) with chemotherapy (HR, 0.77; 95% CI, 0.59-0.99; P = .019).3

Although this analysis confirmed an efficacy benefit with the FLT3 inhibitor, the FDA explained in its ODAC briefing document that it found issues in its review raising concerns over the “credibility” and “generalizability” of the study findings.

The FDA is now scheduled to make a final decision on the application by August 25, 2019.


  1. Daiichi Sankyo’s VANFLYTA® Receives Approval in Japan for the Treatment of Relapsed/Refractory FLT3-ITD AML. Daiichi Sankyo. Published June 18, 2019. https://bit.ly/2KqUki6. Accessed June 18, 2019.
  2. Jorge E. Cortes, MD1, Samer K. Khaled, MD2, Giovanni Martinelli, MD. 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: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 563.
  3. FDA Briefing Document Oncologic Drugs Advisory Committee (ODAC) Meeting May 14, 2019 NDA 212166 Quizartinib Applicant: Daiichi-Sankyo, Inc. Accessed May 14, 2019. https://www.fda.gov/media/124896/download.