Quizartinib, sold under the brand name Vanflyta, is an

anti-cancer medication Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...

used for the treatment of

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

. It is a small molecule

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...

inhibitor. Its molecular target is

FLT3 Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3 with fms standing for "feline McDonough sarcoma"), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in human ...

, also known as CD135 which is a

proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. FLT3 mutations are among the most common mutations in acute myeloid leukemia due to internal tandem duplication of FLT3, and the presence of this mutation is a marker of adverse outcome. The most common side effects of include low white blood cell counts with or without fever, reduced levels of electrolytes (potassium, magnesium or calcium) in blood, increased levels of liver or muscles enzymes, diarrhea, ulcers or redness inside the mouth (mucositis), nausea, abdominal pain, sepsis (serious infection throughout the body and organs), headache, vomiting, and upper respiratory tract infection. It was approved for medical use in Japan in October 2019, in the United States in July 2023, and the European Union in November 2023.

Medical uses

Quizartinib is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

, in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of newly diagnosed

with FLT3 internal tandem duplication (ITD)-positive.

Adverse effects

The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) label includes a

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

noting QT prolongation, torsades de pointes, and cardiac arrest. Quizartinib may cause harm to an unborn baby (embryo-fetal toxicity).

Mechanism of action

Quizartinib selectively inhibits class III receptor tyrosine kinases, including FMS-related tyrosine kinase 3 (

/STK1), colony-stimulating factor 1 receptor (

CSF1R Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). CS ...

/FMS), stem cell factor receptor (SCFR/ KIT), and platelet derived growth factor receptors ( PDGFRs). Mutations cause constant activation of the FLT3 pathway resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.

History

Efficacy of quizartinib with chemotherapy was evaluated in QuANTUM-First (NCT02668653), a randomized, double-blind, placebo-controlled trial of 539 participants with newly diagnosed FLT3 internal tandem duplication positive acute myeloid leukemia. FLT3 internal tandem duplication status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay. Participants were randomized (1:1) to receive quizartinib (n=268) or placebo (n=271) with induction and consolidation therapy and as maintenance monotherapy according to the initial assignment. There was no re-randomization at the initiation of post-consolidation therapy. Participants who proceeded to hematopoietic stem cell transplantation initiated maintenance therapy after hematopoietic stem cell transplantation recovery. The main efficacy outcome measure was overall survival, measured from randomization date until death by any cause. The primary analysis was conducted after a minimum follow-up of 24 months after the last patient was randomized. The trial demonstrated a statistically significant improvement in overall survival for the quizartinib arm azard ratio (HR) 0.78; 95% CI: 0.62, 0.98; 2‑sided p=0.0324 The CR rate in the quizartinib arm was 55% (95% CI: 48.7, 60.9) with a median duration of 38.6 months (95% CI: 21.9, NE), and the CR rate in those receiving placebo was 55% (95% CI: 49.2, 61.4) with a median duration of 12.4 months (95% CI: 8.8, 22.7). The FDA granted the application for quizartinib

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

, fast track, and

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designations.

Clinical trials

It reported good results in 2012, from a phase II clinical trial for refractory acute myeloid leukemia - in participants who went on to have a stem cell transplant. , it has completed seventeen clinical trials, and another eleven are active.

Society and culture

Legal status

The application for quizartinib was denied in the European Union in 2019. In September 2023, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vanflyta, intended for the treatment of acute myeloid leukaemia (AML) that is FLT3-ITD positive. The applicant for this medicinal product is Daiichi Sankyo Europe GmbH. Quizartinib was approved for medical use in Japan in October 2019, in the United States in July 2023, and the European Union in November 2023.

Brand names

Quizartinib is the international nonproprietary name. Quizartinib is sold under the brand name Vanflyta.

References

External links

* {{Authority control 4-Morpholinyl compounds Ethers Heterocyclic compounds with 3 rings Isoxazoles Orphan drugs Receptor tyrosine kinase inhibitors Sulfur heterocycles Tert-butyl compounds Ureas