Osimertinib

Structural formula
General
Non-proprietary name	Osimertinib
other names	N - (2 - {[2- (dimethylamino) ethyl] methylamino} -4-methoxy-5 - {[4- (1-methyl-1 H -indol-3-yl) pyrimidin-2-yl] amino} phenyl) prop -2-enamide AZD-9291 Mereletinib (proposed non-proprietary name until 2015)
Molecular formula	C 28 H 33 N 7 O 2 (osimertinib) C 29 H 37 N 7 O 5 S (osimertinib mesilate)
External identifiers / databases
CAS number 1421373-65-0 (osimertinib) 1421373-66-1 (osimertinib mesilate) PubChem 71496458 ChemSpider 31042598 DrugBank DB09330 Wikidata Q21506464
Drug information
ATC code	L01 XE35
Drug class	Tyrosine kinase inhibitor
properties
Molar mass	499.62 g · mol -1 (Osimertinib)
Melting point	> 188 ° C (decomposition)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 361-317-372 P: 261-262
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Osimertinib is an oral irreversible epidermal growth factor receptor - tyrosine kinase inhibitor of the third generation ( English Epidermal Growth Factor Receptor - tyrosine kinase inhibitor , EGFR-TKI), the selectively both EGFR-TKI-sensitizing and EGFR-T790M-resistance mutations inhibits. It is for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung carcinoma ( English non small cell lung cancer of, NSCLC) with activating mutations epidermal growth factor receptor ( English Epidermal Growth Factor Receptor EGFR) is provided.

EGFR mutation T790M

→ Main article : EGFR mutation T790M

The T790M mutation in exon 20 of the EGFR - gene is the most common (primary or acquired) resistance mutation in NSCLC. Irreversible EGFR inhibitors are characterized by additional strong noncovalent binding motifs and thus have a high potency towards the cysteine ​​‐ mutated L858R / T790M / C797S EGFR enzyme. The most frequently found mutated amino acid position is threonine at position 790 (T790). Usually threonine is replaced by methionine (M). Threonine is a small polar amino acid. Methionine is a larger non-polar amino acid.

Clinical use

Patients with EGFR sensitizing mutations treated with 1st or 2nd generation TKIs should be tested for a T790M mutation at the time of clinical or radiographic progression. The results should guide treatment decisions. Tests for the presence of EGFR-T790M as a resistance mechanism can either preferably of circulating tumor DNA ( English Circulating free DNA , cfDNA) from plasma by means of the Liquid Biopsy or from the DNA from the tissue by means of conventional biopsy be performed.

A positive result of T790M from a cfDNA test can be an indication for therapy using osimertinib to target the T790M mutation. A tissue biopsy can follow if the Liquid Biopsy for T790M is negative.

The dosage consists of one tablet of 80 mg daily. For special cases (e.g. liver or kidney dysfunction) tablets with 40 mg are available.

Unwanted side effects

The most common side effects with osimertinib (which may affect more than 1 in 10 people) are diarrhea , rash , dry skin, paronychia (infection of the nail bed), itching, stomatitis (inflammation of the lining of the mouth) and a decrease in the number of white blood cells and platelets . Osimertinib must not be used with St. John's wort (a herbal medicine used to treat depression ). Osimertinib is a substrate of cytochrome P ₄₅₀ 3A4 (CYP3A4), P-glycoprotein, and breast cancer resistance protein (BCRP, ABCG2).

metabolism

In vitro studies suggest that osimertinib is predominantly metabolised by CYP3A4 and cytochrome P ₄₅₀ 3A5 (CYP3A5) . Two pharmacologically active metabolites (AZ 7550 and AZ 5104) were identified on the basis of in-vitro studies. Osimertinib is broken down mainly via oxidation and dealkylation .

Admission

Therapy with the EGFR tyrosine kinase inhibitor osimertinib resulted in a median progression-free survival of 18.9 months compared with 10.2 months compared to treatment with erlotinib or gefitinib . In November 2015, the US Food and Drug Administration (FDA) granted accelerated approval of osimertinib for the treatment of patients with advanced lung cancer with activating EGFR mutations. The European Commission followed suit with its approval. The drug has been approved in Germany since February 2016, and as a first-line therapeutic since June 7, 2018. The approval is based on the results of the FLAURA study. In addition to the EU, osimertinib is approved as a first-line therapeutic agent in the USA, Japan, Canada, Switzerland, Israel, Mexico, Australia, South Korea and other countries .

Trade name

Tagrisso ^® , ( AstraZeneca ). Osimertinib is contained in the medicinal product as osimertinib mesilat .

further reading

• Features of the drug Tagrisso
• Osimertinib (Tagrisso) in advanced lung cancer with activating EGFR mutations , Health Information Service, Institute for Quality and Efficiency in Health Care (IQWiG) October 15, 2018
• Benefit assessment procedure for the active substance osimertinib (new area of ​​application: non-small cell lung cancer, first-line therapy) , Federal Joint Committee G-BA

Individual evidence

1. ↑ Entry on AZD 9291 (osimertinib) at Toronto Research Chemicals , accessed on September 4, 2019 ( PDF ).
2. ↑ Hazardous substance labeling drug tumor therapy , BGW
3. ↑ J-690167 - Osimertinib , Biosynth. Retrieved February 28, 2019.
4. ↑ Marcel Günther, Michael Juchum, Gerhard Kelter, Heiner Fiebig, Stefan Laufer: Lung cancer: EGFR inhibitors with high effectiveness against the therapy-resistant L858R / T790M / C797S mutant. In: Angewandte Chemie. 128, 2016, p. 11050, doi : 10.1002 / anie.201603736 .
5. ↑ D. Ayeni, K. Politi, SB Goldberg: Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer. In: Clinical Cancer Research . Volume 21, number 17, September 2015, pp. 3818-3820, doi : 10.1158 / 1078-0432.CCR-15-1211 , PMID 26169963 , PMC 4720502 (free full text).
6. ↑ T. Stockley, CA Souza, et. al .: Evidence-based best practices for EGFR T790M testing in lung cancer in Canada. In: Current Oncology . 25, 2018, p. 163, doi : 10.3747 / co.25.4044 .
7. ↑ Tagrisso (osimertinib) , European Medicines Agency , June 2018. Accessed February 27, 2019.
8. ↑ Entry on AZ 7550 at ChemicalBook , accessed on February 28, 2019.
9. ↑ Entry on AZ 5104 at ChemicalBook , accessed February 28, 2019.
10. ↑ Pharmacokinetics Osimertinib , Open Drug Database (ODDB). Retrieved February 28, 2019.
11. ↑ Tagrisso: Procedural steps taken and scientific information after the authorization , European Medicines Agency, accessed on February 28, 2019.
12. ↑ AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA) , ClinicalTrials.gov, US National Library of Medicine, last update January 24, 2019. Retrieved February 27, 2019.
13. ↑ Jean-Charles Soria, Yuichiro Ohe u. a .: Osimertinib in Untreated-Mutated Advanced Non-Small-Cell Lung Cancer. In: The New England Journal of Medicine . 378, 2018, p. 113 ff, doi : 10.1056 / NEJMoa1713137 .
14. ↑ TAGRISSO® (osimertinib) shows significant superiority over standard chemotherapy for non-small cell lung cancer with EGFR T790M mutation , oncotrends. Retrieved March 1, 2019.

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