Gilteritinib: First Global Approval
- 48 Downloads
Gilteritinib (Xospata®) is an orally available small molecule receptor tyrosine kinase inhibitor developed by Astellas Pharma in collaboration with Kotobuki Pharmaceutical for the treatment of acute myeloid leukaemia (AML) harbouring FMS-like tyrosine kinase 3 (FLT3) mutations. Gilteritinib inhibits FLT3 (STK1 or FLK2), AXL (UFO or JTK11) and anaplastic lymphoma kinase (ALK or CD246). Gilteritinib inhibits FLT3 signalling in cells expressing FLT3 internal tandem duplication (ITD), tyrosine kinase domain mutation FLT3-D835Y and the double mutant FLT3-ITD-D835Y, thereby inducing apoptosis. Gilteritinib also binds to and inhibits the wild-type and mutated forms of ALK, resulting in reduced tumour cell proliferation in cancer cell types that overexpress the mutation. Gilteritinib is approved in Japan for the treatment of relapsed or refractory AML with FLT3 mutation. Recently, it was also approved in the USA for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation, as detected by an FDA-approved test. Clinical development of gilteritinib is underway in several countries worldwide. Development for non-small cell lung cancer and solid tumours has been discontinued.
Compliance with Ethical Standards
The preparation of this review was not supported by any external funding.
Conflict of interest
During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.
- 6.Astellas Pharma. Astellas announces approval in Japan for XOSPATA® 40 mg tablets for the treatment of FLT3mut + relapsed or refractory AML [media release]. 21 Sep 2018. https://www.astellas.com/en/news/14271.
- 7.Astellas Pharma. XOSPATA tablets 40 mg: Japanese prescribing information. 2018. http://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/800126_4291053F1021_1_01. Accessed 2018.
- 8.Invivoscribe Technologies. Invivoscribe® receives approval in Japan for its LeukoStrat® CDx FLT3 Mutation Assay to assess acute myeloid leukemia (AML) patients eligible for treatment with Xospata® (gilteritinibfumarate) [media release]. 27 Sep 2018. https://globenewswire.com/news-release/2018/09/27/1577006/0/en/Invivoscribe-Receives-Approval-in-Japan-for-its-LeukoStrat-CDx-FLT3-Mutation-Assay-to-Assess-Acute-Myeloid-Leukemia-AML-Patients-Eligible-for-Treatment-with-Xospata-gilteritinib-fu.html.
- 9.US FDA. FDA approves treatment for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a certain genetic mutation [media release]. 28 Nov 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm627072.htm.
- 10.Astellas Pharma. XOSPATA® (gilteritinib): US Prescribing Information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211349s000lbl.pdf. Accessed 24 Dec 2018.
- 11.Astellas Pharma. Astellas announces preliminary phase 1/2 safety, tolerability and efficacy data for ASP2215 in patients with relapsed or refractory acute myeloid leukemia (AML) [media release]. 30 May 2015. https://newsroom.astellas.us/2015-05-30-Astellas-Announces-Preliminary-Phase-1-2-Safety-Tolerability-And-Efficacy-Data-For-ASP2215-In-Patients-With-Relapsed-Or-Refractory-Acute-Myeloid-Leukemia-AML.
- 15.Ueno Y, Kaneko N, Saito R, et al. ASP2215, a novel FLT3/AXL inhibitor: preclinical evaluation in combination with cytarabine and anthracycline in acute myeloid leukemia (AML) [abstract no. 7071]. J Clin Oncol. 2014;32(15 Suppl).Google Scholar
- 16.Ueno Y, Mori M, Kamiyama Y, et al. Gilteritinib (ASP2215), a novel FLT3/AXL inhibitor: preclinical evaluation in combination with azacitidine in acute myeloid leukemia. Blood. 2016;128(22):2830.Google Scholar
- 17.Knight T, Qiao X, Edwards H, et al. Novel therapy for FLT3-ITD acute myeloid leukemia utilizing the combination of CUDC-907 and gilteritinib [abstract no. 1427]. Blood. 2018;132(Suppl 1).Google Scholar
- 18.Cloe A, Larson RA, Cheng JX. FLT3 inhibitors for the treatment of acute myeloid leukemia: an evaluation of efficacy of target inhibition and relationship to disease progression [abstract no. 4940]. Blood Conf. 2015;126(23).Google Scholar
- 19.McMahon CM, Canaani J, Rea B, et al. Mechanisms of acquired resistance to gilteritinib therapy in relapsed and refractory FLT3-mutated acute myeloid leukemia [abstract no. 295]. Blood. 2017;130(Suppl 1).Google Scholar
- 20.McMahon CM, Ferng TT, Canaani J, et al. RAS mutations are the dominant mechanism of secondary resistance to gilteritinib therapy for relapsed/refractory FLT3-mutated AML [abstract no. S817]. In: 23rd congress of the European haematology association. 2018.Google Scholar
- 22.US National Institutes of Health. ClinicalTrials.gov (NCT02421939). 2019. https://clinicaltrials.gov/ct2/show/NCT02421939. Accessed 22 Jan 2019.
- 23.Jessica A, Perl A, Cortes J, et al. Deep molecular response to gilteritinib improves survival in FLT3 mutation-positive relapsed/refractory acute myeloid leukemia [abstract no. S110]. Haematologica. 2017;102(Suppl 2):6.Google Scholar
- 25.Levis MJ, Perl AE, Altman JK, et al. Impact of minimal residual disease and achievement of complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival following treatment with gilteritinib in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3 mutations [abstract no. 1458]. Blood. 2018;(132).Google Scholar
- 26.Canaani J, Rea B, Sargent R, et al. Differentiation response to gilteritinib (ASP2215) in relapsed/refractory FLT3 mutated acute myeloid leukemia patients is associated with co-mutations in NPM1 and DNMT3A [abstract no. P188]. Haematologica. 2016;101(Suppl 1):42.Google Scholar
- 28.Cortes JE, Altman J, Ritchie EK, et al. A phase II/III, multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy [abstract no. TPS7068]. J Clin Oncol Conf. 2017;35(15 Suppl.).Google Scholar
- 29.Esteve J, Schots R, Del Castillo TB, et al. Multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine in newly diagnosed FLT3 mutated (FLT3 mut+) acute myeloid leukemia (AML) patienyts ineligible for intensive induction chemotherapy: findings from the safety cohort [abstract no. 2736]. Blood. 2018;132.Google Scholar
- 30.Pratz K, Cherry M, Altman JK, et al. Preliminary results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML) [abstract no. 722]. Blood. 2017;130(Suppl 1).Google Scholar
- 31.Pratz KW, Cherry M, Altman JK, et al. Updated results from a phase I study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML) [abstract no. 564]. Blood. 2018;132.Google Scholar
- 32.Invivoscribe Technologies. Invivoscribe Technologies announces companion diagnostic agreement [media release]. 28 Apr 2015. http://www.marketwired.com/press-release/invivoscribe-technologies-announces-companion-diagnostic-agreement-2013950.htm.