Quizartinib: Difference between revisions

{{Short description|Medication}}

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| Legal_US_comment = <ref name="Vanflyta FDA label">{{cite web | title=Vanflyta- quizartinib tablet, film coated | website=DailyMed | date=26 July 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29cdbcfe-497d-4e78-bb7b-2d4acafe8e86 | access-date=6 August 2023 | archive-date=7 August 2023 | archive-url=https://web.archive.org/web/20230807043902/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=29cdbcfe-497d-4e78-bb7b-2d4acafe8e86 | url-status=live }}</ref><ref name="FDA quizartinib" />

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| Legal_EU_comment = <ref name="Vanflyta EPAR">{{cite web | title=Vanflyta EPAR | website=European Medicines Agency | date=21 November 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/vanflyta-0 | access-date=22 November 2023 | archive-date=22 November 2023 | archive-url=https://web.archive.org/web/20231122055008/https://www.ema.europa.eu/en/medicines/human/EPAR/vanflyta-0 | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref name="Vanflyta Product information">{{cite web | title=Vanflyta Product information | website=Union Register of medicinal products | date=7 November 2023 | url=https://ec.europa.eu/health/documents/community-register/html/h1768.htm | access-date=13 November 2023 | archive-date=13 November 2023 | archive-url=https://web.archive.org/web/20231113031948/https://ec.europa.eu/health/documents/community-register/html/h1768.htm | url-status=live }}</ref>

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'''Quizartinib''', sold under the brand name '''Vanflyta''', is an [[anti-cancer medication]] used for the treatment of [[acute myeloid leukemia]].<ref name="FDA quizartinib">{{cite web |date=20 July 2023 |title=FDA approves quizartinib for newly diagnosed acute myeloid leukemia |url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia |accessdate=21 July 2023 |publisher=U.S. [[Food and Drug Administration]] (FDA) |archive-date=21 July 2023 |archive-url=https://web.archive.org/web/20230721005023/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-quizartinib-newly-diagnosed-acute-myeloid-leukemia |url-status=live }} {{PD-notice}}</ref>

It is a small molecule [[receptor tyrosine kinase]] inhibitor. Its molecular target is [[FLT3]], also known as [[CD135]] which is a [[proto-oncogene]].<ref>{{cite journal | vauthors = Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J, Zarrinkar PP, Patel HK, Bhagwat SS | title = Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N'-<nowiki/>{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor | journal = Journal of Medicinal Chemistry | date = December 2009 | volume = 52 | issue = 23 | pages = 7808–7816 | doi=10.1021/jm9007533 | pmid=19754199 }}</ref> 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.<ref>{{cite journal | vauthors = Levis M, Murphy KM, Pham R, Kim KT, Stine A, Li L, McNiece I, Smith BD, Small D | title = Internal tandem duplications of the FLT3 gene are present in leukemia stem cells | journal = Blood | volume = 106 | issue = 2 | pages = 673–80 | date = July 2005 | pmid = 15797998 | pmc = 1895185 | doi = 10.1182/blood-2004-05-1902 }}</ref>

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.<ref name="Vanflyta FDA snapshot">{{cite web | title=Drug Trials Snapshots: Vanflyta | website=U.S. [[Food and Drug Administration]] (FDA) | date=20 July 2023 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-vanflyta | access-date=18 April 2024}} {{PD-notice}}</ref>

It was approved for medical use in Japan in October 2019,<ref name="Daiichi Sankyo PR">{{cite press release |title=Daiichi Sankyo Launches FLT3 Inhibitor Vanflyta in Japan for the Treatment of Patients with Relapsed/Refractory FLT3-ITD AML |url=https://www.daiichisankyo.com/media/press_release/detail/index_3169.html |access-date=16 February 2021 |archive-date=10 August 2023 |archive-url=https://web.archive.org/web/20230810224925/https://www.daiichisankyo.com/media/press_release/detail/index_3169.html |url-status=live }}</ref> in the United States in July 2023,<ref name="FDA quizartinib" /> and the European Union in November 2023.<ref name="Vanflyta EPAR" />

== Medical uses ==

Quizartinib is [[indicated]], in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of newly diagnosed [[acute myeloid leukemia]] with FLT3 internal tandem duplication (ITD)-positive.<ref name="FDA quizartinib" /><ref name="Vanflyta EPAR" />

== Adverse effects ==

The US [[Food and Drug Administration]] (FDA) label includes a [[boxed warning]] noting QT prolongation, torsades de pointes, and cardiac arrest.<ref name="FDA quizartinib" /><ref name="Vanflyta FDA snapshot" />

Quizartinib may cause harm to an unborn baby (embryo-fetal toxicity).<ref name="Vanflyta FDA snapshot" />

== Mechanism of action ==

Quizartinib selectively inhibits class III receptor tyrosine kinases, including FMS-related tyrosine kinase 3 ([[FLT3]]/STK1), colony-stimulating factor 1 receptor ([[CSF1R]]/FMS), [[stem cell factor receptor]] (SCFR/[[KIT (gene)|KIT]]), and platelet derived growth factor receptors ([[PDGFR]]s).<ref name="pmid23497317">{{cite journal | vauthors = Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Döhner H, Döhner K, Schittenhelm MM | title = Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms | journal = Molecular Cancer | volume = 12 | issue = | pages = 19 | date = March 2013 | pmid = 23497317 | pmc = 3637582 | doi = 10.1186/1476-4598-12-19 | doi-access = free }}</ref>

Mutations cause constant activation of the FLT3 pathway resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.<ref name="pmid23497317" />

== 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.<ref name="FDA quizartinib" /> 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.<ref name="FDA quizartinib" /> 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.<ref name="FDA quizartinib" /> There was no re-randomization at the initiation of post-consolidation therapy.<ref name="FDA quizartinib" /> Participants who proceeded to hematopoietic stem cell transplantation initiated maintenance therapy after hematopoietic stem cell transplantation recovery.<ref name="FDA quizartinib" />

The main efficacy outcome measure was overall survival, measured from randomization date until death by any cause.<ref name="FDA quizartinib" /> The primary analysis was conducted after a minimum follow-up of 24 months after the last patient was randomized.<ref name="FDA quizartinib" /> The trial demonstrated a statistically significant improvement in overall survival for the quizartinib arm [hazard ratio (HR) 0.78; 95% CI: 0.62, 0.98; 2‑sided p=0.0324].<ref name="FDA quizartinib" /> 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).<ref name="FDA quizartinib" />

The FDA granted the application for quizartinib [[priority review]], [[Fast track (FDA)|fast track]], and [[orphan drug]] designations.<ref name="FDA quizartinib" />

=== 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.<ref name=ASH2012>{{cite web |url=http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36351 |title=Drug Tames Refractory AML. ASH Dec 2012 |date=9 December 2012 |access-date=16 December 2012 |archive-date=8 August 2014 |archive-url=https://web.archive.org/web/20140808060444/http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36351 |url-status=live }}</ref>{{Unreliable medical source|date=August 2023}}

{{As of|2023|July}}, it has completed seventeen clinical trials, and another eleven are active.<ref>{{cite web |url=https://clinicaltrials.gov/ct2/results?term=quizartinib&Search=Search |title=Quizartinib studies |access-date=20 February 2017 |archive-date=21 February 2017 |archive-url=https://web.archive.org/web/20170221105900/https://clinicaltrials.gov/ct2/results?term=quizartinib&Search=Search |url-status=live }}</ref>

== Society and culture ==

=== Legal status ===

The application for quizartinib was denied in the European Union in 2019.<ref>{{cite web | title=Vanflyta | website=European Medicines Agency | date=6 January 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/vanflyta | access-date=6 August 2023 | archive-date=27 January 2023 | archive-url=https://web.archive.org/web/20230127084249/https://www.ema.europa.eu/en/medicines/human/EPAR/vanflyta | url-status=live }}</ref>

In September 2023, the [[Committee for Medicinal Products for Human Use]] of the [[European Medicines Agency]] 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.<ref name="Vanflyta EPAR" /> The applicant for this medicinal product is Daiichi Sankyo Europe GmbH.<ref name="Vanflyta EPAR" />

Quizartinib was approved for medical use in Japan in October 2019,<ref name="Daiichi Sankyo PR" /> in the United States in July 2023,<ref name="FDA quizartinib" /> and the European Union in November 2023.<ref name="Vanflyta EPAR" /><ref name="Vanflyta Product information" />

=== Brand names ===

Quizartinib is the [[international nonproprietary name]].<ref>{{cite journal | vauthors = ((World Health Organization)) | year = 2011 | title = International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 66 | journal = WHO Drug Information | volume = 25 | issue = 3 | hdl = 10665/74683 | hdl-access = free | author-link = World Health Organization }}</ref>

Quizartinib is sold under the brand name Vanflyta.<ref name="Vanflyta FDA label" /><ref name="Vanflyta EPAR" />

{{Reflist}}

== Further reading ==

* {{cite journal | vauthors = Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, Wang PN, Mitov T, Hanyok J, Kamel YM, Rohrbach JE, Liu L, Benzohra A, Lesegretain A, Cortes J, Perl AE, Sekeres MA, Dombret H, Amadori S, Wang J, Levis MJ, Schlenk RF | title = Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial | journal = Lancet | volume = 401 | issue = 10388 | pages = 1571–1583 | date = May 2023 | pmid = 37116523 | doi = 10.1016/S0140-6736(23)00464-6 | s2cid = 258314572 }}

== External links ==

* {{ClinicalTrialsGov|NCT02668653|Quizartinib With Standard of Care Chemotherapy and as Continuation Therapy in Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (AML) (QuANTUM-First)}}

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[[Category:Receptor tyrosine kinase inhibitors]]

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