Osimertinib

Osimertinib (previously known as mereletinib; trade name Tagrisso)[2][3] is a medication used to treat non-small-cell lung carcinomas with specific mutations.[4][5] It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. Developed by AstraZeneca, the medication was approved as a cancer treatment in 2017 by both the Food and Drug Administration and the European Commission.

Osimertinib
Clinical data
Trade namesTagrisso, Tagrix
Other namesAZD9291
AHFS/Drugs.comtagrisso
License data
Routes of
administration		Oral tablets
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingProbably high[1]
MetabolismOxidation (CYP3A)
Elimination half-life48 hours
ExcretionFeces (68%), urine (14%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
PDB ligand
Chemical and physical data
FormulaC28H33N7O2
Molar mass499.619 g·mol−1
3D model (JSmol)

Medical uses

Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), if the cancer cells are positive for the T790M mutation in the gene coding for EGFR or for activating EGFR mutations.[1] The T790M mutation may be de novo or acquired following first-line treatment with other tyrosine kinase inhibitors (TKIs), such as gefitinib and afatinib.[6]

In the USA, EGFR exon 19 deletions, exon 21 L858R mutations or the T790M status of the patient prior to treatment with osimertinib must be detected by a federally approved companion diagnostic test.[1] The Food and Drug Administration (FDA) has approved FoundationOne CDx as one available companion diagnostic test for this purpose.[7] In Europe and elsewhere, activating EGFR mutations or T790M mutations may be determined by a validated test.[8]

In people treated with osimertinib, resistance usually develops within approximately 10 months.[9] Resistance mediated by an exon 20 C797S mutation accounts for the majority of resistance cases.[10]

It can cause fetal harm, so should not be used in women who are pregnant, and women who take it should avoid becoming pregnant.[1][11]

Caution should be taken in people with a history of interstitial lung disease (ILD), as they were excluded from clinical trials, since the drug can cause severe ILD or pneumonitis. Caution should also be taken in people with a predisposition to long QT syndrome as the drug can provoke this.[1]

Adverse effects

Very common (greater than 10% of clinical trial subjects) adverse effects include diarrhea, stomatitis, rashes, dry or itchy skin, infections where finger or toenails abut skin, low platelet counts, low leukocyte counts, and low neutrophil counts.[12]

Common (between 1% and 10% of clinical trial subjects) adverse effects include interstitial lung disease.[12]

Interactions

Osimertinib is metabolized by CYP3A4 and CYP3A5, so substances that strongly inhibit either enzyme, like macrolide antibiotics, antifungals, and antivirals may increase exposure to osimertinib, and substances like rifampicin that activate either enzyme may decrease the effectiveness of osimertinib.[1][12]

Pharmacology

Osimertinib binds irreversibly to epidermal growth factor receptor proteins expressed by EGFR with a T790M mutation;[12] it also binds irreversibly to EGFR with a L858R mutation and with an exon 19 deletion.[1]

It exhibits linear pharmacokinetics; the median time to Cmax is 6 hours (range 3–24 hours). The estimated mean half-life is 48 hours, and oral clearance (CL/F) is 14.3 (L/h).[1] 68% of elimination is by feces and 14% by urine.[1]

Chemistry

Osimertinib is provided as the mesylate; the chemical formula is C28H33N7O2·CH4O3S, and the molecular weight is 596 g/mol. The chemical name is N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt.[1]

History

The drug discovery program that led to osimertinib started in 2009 and yielded the drug by 2012; the process was structure-driven and aimed to find a third generation EGFR inhibitor that would selectively target the T790M form of the EGFR receptor.[13]

Osimertinib was designated as a Breakthrough Therapy in April 2014 based on Phase I trial results,[13] and the drug was provisionally approved under the FDA accelerated approval program with a priority review voucher, in November 2015.[14]

In February 2016 the EMA provisionally approved osimertinib under an accelerated process—the first approval under the program.[13]

Society and culture

At launch, Astrazeneca priced the drug at $12,750 per month.[15]:59

Research

As of  2020, several clinical trials were ongoing.[16]

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References
  1. "TAGRISSO FDA Label". nctr-crs.fda.gov. FDA. December 2019. Retrieved 2020-04-27.
  2. "Osimertinib". AdisInsight. Archived from the original on 23 August 2018. Retrieved 27 February 2017.
  3. "Proposed INN: List 113" (PDF). International Nonproprietary Names for Pharmaceutical Substances (INN). 29 (2): 285. 2015. Archived (PDF) from the original on 28 April 2017. Retrieved 16 November 2015.
  4. Ayeni D, Politi K, Goldberg SB (September 2015). "Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer". Clinical Cancer Research. 21 (17): 3818–20. doi:10.1158/1078-0432.CCR-15-1211. PMC 4720502. PMID 26169963.
  5. Tan CS, Gilligan D, Pacey S (September 2015). "Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer". The Lancet. Oncology. 16 (9): e447–e459. doi:10.1016/S1470-2045(15)00246-6. PMID 26370354.
  6. Xu M, Xie Y, Ni S, Liu H (May 2015). "The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)". Annals of Translational Medicine. 3 (7): 96. doi:10.3978/j.issn.2305-5839.2015.03.60. PMC 4430733. PMID 26015938.
  7. Health, Center for Devices and Radiological. "In Vitro Diagnostics - List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)". www.fda.gov. Archived from the original on 2018-01-25. Retrieved 2018-01-17.
  8. "European Tagrisso information" (PDF). European Medicines Agency. Archived (PDF) from the original on 2018-01-17. Retrieved 2018-01-17.
  9. Patel H, Pawara R, Ansari A, Surana S (December 2017). "Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance". European Journal of Medicinal Chemistry. 142: 32–47. doi:10.1016/j.ejmech.2017.05.027. PMID 28526474.
  10. Wang S, Song Y, Liu D (January 2017). "EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance". Cancer Letters. 385: 51–54. doi:10.1016/j.canlet.2016.11.008. PMID 27840244.
  11. Bollinger, Meredith K; Agnew, Amanda S; Mascara, Gerard P (July 2018). "Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation". Journal of Oncology Pharmacy Practice. 24 (5): 379–388. doi:10.1177/1078155217712401. ISSN 1078-1552.
  12. "UK label". UK Electronic Medicines Compendium. 26 January 2017. Archived from the original on 27 February 2017. Retrieved 27 February 2017.
  13. Yver A (June 2016). "Osimertinib (AZD9291)-a science-driven, collaborative approach to rapid drug design and development". Annals of Oncology. 27 (6): 1165–70. doi:10.1093/annonc/mdw129. PMID 26961148.
  14. "Approved Drugs - Osimertinib". FDA Center for Drug Evaluation and Research. November 13, 2015. Archived from the original on February 27, 2017. Retrieved February 27, 2017.
  15. "AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report Priority Area 02: Cancer" (PDF). AHRQ. December 2015. Archived from the original (PDF) on 2017-04-30. Retrieved 2017-02-27.
  16. "Search of: Osimertinib - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-04-27.
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