Afatinib

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Not to be confused with apatinib.
Afatinib
Afatinib2DACS.svg
Systematic (IUPAC) name
N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide
Clinical data
Trade names Gilotrif, Giotrif
AHFS/Drugs.com Multum Consumer Information
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: C
  • US: D (Evidence of risk)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Protein binding 95%
Metabolism CYP not involved
Biological half-life 37 hours
Excretion Faeces (85%), urine (4%)
Identifiers
CAS Number 850140-72-6 YesY[Drugbank]
ATC code L01XE13 (WHO)
PubChem CID: 10184653
IUPHAR/BPS 5667
DrugBank DB08916 YesY
ChemSpider 8360155 YesY
UNII 41UD74L59M YesY
KEGG D09724
ChEBI CHEBI:61390 YesY
ChEMBL CHEMBL1173655 YesY
Synonyms BIBW 2992
Chemical data
Formula C24H25ClFN5O3
Molecular mass 485.937 g/mol
  • CN(C)C\C=C\C(=O)Nc3cc1c(Nc(cc2Cl)ccc2F)ncnc1cc3OC4COCC4
  • InChI=1S/C24H25ClFN5O3/c1-31(2)8-3-4-23(32)30-21-11-17-20(12-22(21)34-16-7-9-33-13-16)27-14-28-24(17)29-15-5-6-19(26)18(25)10-15/h3-6,10-12,14,16H,7-9,13H2,1-2H3,(H,30,32)(H,27,28,29)/b4-3+/t16-/m0/s1 YesY
  • Key:ULXXDDBFHOBEHA-CWDCEQMOSA-N YesY
  (verify)

Afatinib (INN; trade name Gilotrif in the US and Giotrif in Europe, previously Tomtovok and Tovok[1]) is a drug approved in United States, Europe, Taiwan, Mexico, Chile and Japan as well as other countries for the first-line treatment of patients with distinct types of metastatic (EGFR mutation positive) non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim.[2][3][4] It acts as an irreversible covalent inhibitor of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and erbB-2 (HER2).

Medical uses

It has received regulatory approval for use as a treatment for non-small cell lung cancer,[5][6][7][8] although there is emerging evidence to support its use in other cancers such as breast cancer.[9]

Adverse effects

Adverse effects by frequency include:[5][6][7][10][8]

Very common (>10% frequency)

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Common (1–10% frequency)

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Uncommon (0.1-1% frequency)

Mechanism of action

Like lapatinib and neratinib, afatinib is a protein kinase inhibitor that also irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation TKIs like erlotinib or gefitinib, but also against mutations such as T790M which are not sensitive to these standard therapies.[11] Because of its additional activity against Her2, it is being investigated for breast cancer as well as other EGFR and Her2 driven cancers.[3]

Afatinib covalently binds to cysteine number 797 of the epidermal growth factor receptor (EGFR) via a Michael addition (IC50 = 0.5 nM).[12]

Clinical trials

In March 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug.[13] Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival.[14] In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.[15]

In January 2015 a Phase III trial in people with NSCLC suggested the drug extended life expectancy in stage IV NSCLC Adenocarcinoma with EGFR Mutation type del 19-positive tumors, compared to cisplatin-based chemotherapy by a year (33 months vs. 21 months).[16]

Phase II results for breast cancer that over-expresses the protein human epidermal growth factor receptor 2 (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib.[9] Double-blind Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.[17]

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (German)
  13. ↑ Clinical trial number NCT01085136 for "LUX-Lung 5: BIBW 2992 Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following BIBW 2992 Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib" at ClinicalTrials.gov
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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