Daiichi Sankyo Company announced the outcome of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) to discuss the company's New Drug Application (NDA) for quizartinib for the treatment of adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

Three committee members voted yes and 8 committee members voted no when asked if the results from the pivotal phase 3 QuANTUM-R study demonstrated that treatment with quizartinib provides a benefit that outweighs the safety risks for patients with relapsed/refractory FLT3-ITD AML.

"While we are disappointed by the outcome of today's ODAC vote, we will work closely with the FDA as it completes the review of our submission," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Patients with relapsed/refractory FLT3-ITD AML are facing a very aggressive disease with poor prognosis, and we continue to believe that quizartinib could offer an important additional treatment option that specifically targets FLT3-ITD, a driver mutation in AML."

The FDA is not bound by the recommendations of the advisory committee. The NDA for quizartinib is currently under Priority Review in the U.S., and the FDA is expected to make a decision on approval by the Prescription Drug User Fee Act (PDUFA) date of August 25, 2019. The NDA submission of quizartinib is based on the results of the pivotal phase 3 QuANTUM-R study, which was the first randomized phase 3 study to show that a FLT3 inhibitor prolonged overall survival as an oral, single agent compared to chemotherapy in patients with relapsed/refractory FLT3-ITD AML.

In the quizartinib QuANTUM-R study, the median treatment duration with quizartinib was 4 cycles of 28 days each versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse drug reactions (>30 percent, any Grade) in patients treated with quizartinib included infections, bleeding, nausea, asthenic conditions, pyrexia, febrile neutropenia, and vomiting, and the most common Grade ≥ 3 adverse drug reactions (>20 percent) were infection and febrile neutropenia. The most common laboratory adverse reactions (incidence >50 percent) were decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, decreased neutrophil count, and decreased platelet count. QTcF >500 msec occurred in 8 patients (3.3 percent) and 2 out of 241 patients discontinued quizartinib due to QTcF prolongation. There were no reported events of Grade 4 QTcF prolongation (Torsades de Pointes, sudden death or cardiac arrest) in the quizartinib arm. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 In the U.S. this year, it is estimated that there will be more than 19,000 new diagnoses of AML and more than 10,000 deaths from AML. The five-year survival rate of AML reported from 2007 to 2013 was approximately 27 percent, which was the lowest of all leukemias.

FLT3 gene mutations are one of the most common genetic abnormalities in AML.3 FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML. FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML. Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.

Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective type II FLT3 inhibitor currently under regulatory review with the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of adult patients with relapsed/refractory AML which is FLT3-ITD positive. Quizartinib has been granted Priority Review and Breakthrough Therapy designation for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, and Fast Track designation for the treatment of relapsed/refractory AML by the FDA. Quizartinib also has been granted Orphan Drug designation by both the FDA and the European Commission (EC) for the treatment of AML and by the Japan MHLW for the treatment of FLT3-mutated AML.

Quizartinib is also in phase 3 development in combination with standard chemotherapy in newly-diagnosed FLT3-ITD AML (QuANTUM-First) in the U.S., EU and Japan; phase 1/2 development for pediatric and young adult relapsed/refractory FLT3-ITD AML in North America and the EU; and phase 1 development in combination with an investigational MDM2 inhibitor, milademetan, for relapsed/refractory FLT3-ITD AML and newly-diagnosed FLT3-ITD AML unfit for intensive chemotherapy in the U.S. and Japan.

Quizartinib and milademetan are investigational agents that have not been approved for any indication in any country. Safety and efficacy have not been established.

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