Avapritinib Explained

Pronounce:A va PRI ti nib
Tradename:Ayvakit, Ayvakyt
Dailymedid:Avapritinib
Routes Of Administration:By mouth
Class:Antineoplastic agent
Atc Prefix:L01
Atc Suffix:EX18
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Eu Comment:[1]
Cas Number:1703793-34-3
Pubchem:118023034
Drugbank:DB15233
Chemspiderid:58828673
Unii:513P80B4YJ
Kegg:D11279
Chembl:4204794
Synonyms:BLU-285, BLU285
Iupac Name:(1S)-1-(4-fluorophenyl)-1-(2-pyrimidin5-yl)ethan-1-amine| C = 26 | H = 27 | F = 1 | N = 10| SMILES = Cn1cc(-c2cc3c(N4CCN(c5ncc(C(C)(N)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1| StdInChI = 1S/C26H27FN10/c1-26(28,20-3-5-22(27)6-4-20)21-13-29-25(30-14-21)36-9-7-35(8-10-36)24-23-11-18(16-37(23)33-17-31-24)19-12-32-34(2)15-19/h3-6,11-17H,7-10,28H2,1-2H3/t26-/m0/s1| StdInChI_comment = | StdInChIKey = DWYRIWUZIJHQKQ-SANMLTNESA-N| density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.[2] [3] Avapritinib is a kinase inhibitor.

Common side effects include edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash and dizziness.

Medical uses

Avapritinib is indicated for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring the platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.

Avapritinib is also indicated for the treatment of adults with advanced systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia (MCL).[4]

History

The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020.[5] [6] The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation. The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.

Avapritinib was approved based on the results from the Phase I NAVIGATOR[7] [8] clinical trial involving 43 subjects with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation. Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).

The FDA approved avapritinib based on evidence from one clinical trial (NCT02508532) of 204 subjects with GIST. The trial was conducted at 17 sites in the United States, Europe and Asia.

Avapritinib showed a median PFS of 4.2 months compared to 5.6 months for regorafenib. The difference in median PFS between the avapritinib and regorafenib groups was not statistically significant. The overall response rate was 17 percent for the avapritinib group and 7 percent for the regorafenib group. The VOYAGER trial evaluated the efficacy and safety of avapritinib (N=240) versus regorafenib (N=236) in patients with third- or fourth-line GIST.[9]

Avapritinib was approved for medical use in the European Union in September 2020.[10]

Ayvakit was granted approval for advanced systemic mastocytosis by the FDA in June 2021.[11]

Further reading

  • Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV . 3 . Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines . Mol. Pharm. . 16 . 7 . 3040–3052 . July 2019 . 31117741 . 10.1021/acs.molpharmaceut.9b00274 . 6620786 .
  • Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schöffski P . 3 . Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors . Clin. Cancer Res. . 25 . 2 . 609–618 . January 2019 . 30274985 . 10.1158/1078-0432.CCR-18-1858 . free .

External links

  • Web site: Avapritinib . NCI Dictionary of Cancer Terms . National Cancer Institute .
  • Web site: Avapritinib . National Cancer Institute . 28 January 2020 .

Notes and References

  1. Web site: Ayvakyt Product information . Union Register of medicinal products . 3 March 2023 . 5 March 2023 . https://web.archive.org/web/20230305055227/https://ec.europa.eu/health/documents/community-register/html/h1473.htm . live .
  2. Web site: Ayvakit- avapritinib tablet, film coated . DailyMed . 21 January 2020 . 29 September 2020 . 27 September 2020 . https://web.archive.org/web/20200927110120/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=645c887c-8cd4-4623-8da9-ac223d71a8b9 . live .
  3. FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors . U.S. Food and Drug Administration (FDA) . 9 January 2020 . https://web.archive.org/web/20200111062447/https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-rare-mutation-patients-gastrointestinal-stromal-tumors . 11 January 2020 . live . 9 January 2020.
  4. Web site: FDA approves avapritinib for advanced systemic mastocytosis . U.S. Food and Drug Administration (FDA) . 16 June 2021 . 16 June 2021 . 16 June 2021 . https://web.archive.org/web/20210616194112/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avapritinib-advanced-systemic-mastocytosis . live .
  5. Web site: Drug Trial Snapshot: Ayvakit . U.S. Food and Drug Administration (FDA) . 9 January 2020 . 24 January 2020 . 24 January 2020 . https://web.archive.org/web/20200124192756/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-ayvakit . live .
  6. Web site: Drug Approval Package: Ayvakit . U.S. Food and Drug Administration (FDA) . 13 February 2020 . 16 June 2021 . 13 April 2021 . https://web.archive.org/web/20210413043014/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212608Orig1s000TOC.cfm . live .
  7. Blueprint Medicines Announces FDA Approval of Ayvakit (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor . Blueprint Medicines Corporation . 9 January 2020 . https://web.archive.org/web/20200111062542/https://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-fda-approval-ayvakittm-avapritinib . 11 January 2020 . live . 9 January 2020.
  8. Blueprint Medicines Announces Updated NAVIGATOR Trial Results in Patients with Advanced Gastrointestinal Stromal Tumors Supporting Development of Avapritinib Across All Lines of Therapy . Blueprint Medicines Corporation . 15 November 2018 . https://web.archive.org/web/20200110062108/https://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-updated-navigator-trial-results . 10 January 2020 . live . 9 January 2020.
  9. Blueprint Medicines Announces Top-line Results from Phase 3 VOYAGER Trial of Avapritinib versus Regorafenib in Patients with Advanced Gastrointestinal Stromal Tumor. Blueprint Medicines Corporation. 28 April 2020. 16 June 2021. 24 June 2021. https://web.archive.org/web/20210624200739/https://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-top-line-results-phase-3-voyager. live.
  10. Web site: Ayvakyt EPAR . European Medicines Agency (EMA) . 20 July 2020 . 29 September 2020 . 1 November 2020 . https://web.archive.org/web/20201101011648/https://www.ema.europa.eu/en/medicines/human/EPAR/ayvakyt . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. Web site: 16 June 2021. FDA approves avapritinib for advanced systemic mastocytosis. U.S. Food and Drug Administration (FDA) . 16 June 2021. 16 June 2021. https://web.archive.org/web/20210616194112/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avapritinib-advanced-systemic-mastocytosis. live.