Afatinib

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Afatinib
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 Tomtovok
Pregnancy cat.  ?
Legal status Investigational
Routes Oral
Pharmacokinetic data
Bioavailability 90%
Metabolism CYP not involved
Half-life 34 hrs
Identifiers
CAS number 439081-18-2 N
ATC code L01XE13
PubChem CID 10184653
ChemSpider 8360155 YesY
UNII 41UD74L59M YesY
ChEBI CHEBI:61390 YesY
ChEMBL CHEMBL1173655 YesY
Synonyms BIBW 2992
Chemical data
Formula C24H25ClFN5O3 
Mol. mass 485.937 g/mol
 N (what is this?)  (verify)

Afatinib[1] (INN; planned trade name Tomtovok, previously Tovok[2]) is a candidate drug against non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim.[3][4] As of July 2012, it is undergoing Phase III clinical trials for this indication and breast cancer,[5] as well as Phase II trials for prostate[6] and head and neck cancer,[7] and a Phase I glioma trial.[8] Afatinib is not a first-line treatment; it is only used after other therapies have failed.

In October 2010 a Phase III trial in NSCLC patients called Lux-Lung 5 began with this drug.[9] Fall 2010 interim results suggested the drug extended progression-free survival threefold compared to placebo, but did not extend overall survival.[10] In May 2012, the Phase IIb/III trial Lux-Lung 1 came to the same conclusion.[11]

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.[12] 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.[13]

Mechanism of action [edit]

Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that 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 those not sensitive to these standard therapies. Because of its additional activity against Her2, it is investigated for breast cancer as well as other EGFR and Her2 driven cancers.[4]

Afatinib covalently binds to cysteine number 797 of the epidermal growth factor receptor (EGFR) via a Michael addition (IC50 = 0.5 nM).[14]

References [edit]

  1. ^ "Afatinib (BIBW 2992) triples progression free survival in phase III study in lung cancer patients". World Pharma News. 12 October 2010. 
  2. ^ "Afatinib (BIBW-2992, Tomtovok) wins a battle (PFS) but loses the war (OS) for EGFR TKI-sensitive patients". GRACE. 18 October 2010. 
  3. ^ H. Spreitzer (May 13, 2008). "Neue Wirkstoffe - Tovok". Österreichische Apothekerzeitung (in German) (10/2008): 498. 
  4. ^ a b Minkovsky N, Berezov A (December 2008). "BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors". Curr Opin Investig Drugs 9 (12): 1336–46. PMID 19037840. 
  5. ^ ClinicalTrials.gov NCT01125566 LUX-Breast 1: BIBW 2992 (Afatinib) in HER2-positive Metastatic Breast Cancer Patients After One Prior Herceptin Treatment
  6. ^ ClinicalTrials.gov NCT01320280 BIBW 2992 (Afatinib) for the Treatment of Patients With HER2-positive, Hormone-refractory Prostate Cancer
  7. ^ ClinicalTrials.gov NCT01345669 LUX-Head&Neck 2: A Phase III Trial of Afatinib (BIBW 2992) Versus Placebo for the Treatment of Head and Neck Squamous Cell Cancer After Treatment With Chemo-radiotherapy
  8. ^ ClinicalTrials.gov NCT00977431 Open Label Trial to Explore Safety of Combining Afatinib (BIBW 2992) and Radiotherapy With or Without Temozolomide in Newly Diagnosed Glioblastoma Multiform
  9. ^ ClinicalTrials.gov NCT01085136 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
  10. ^ "Afatinib (BIBW 2992*) Triples Progression Free Survival in Phase III Study in Lung Cancer Patients". BusinessWire. 11 October 2010. 
  11. ^ Miller, VA; Hirsh, V; Cadranel, J; Chen, YM; Park, K; Kim, SW; Zhou, C; Su, WC et al. (2012). "Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial". The lancet oncology 13 (5): 528–38. doi:10.1016/S1470-2045(12)70087-6. PMID 22452896. 
  12. ^ Lin, Nancy U.; Winer, Eric P.; Wheatley, Duncan; Carey, Lisa A.; Houston, Stephen; Mendelson, David; Munster, Pamela; Frakes, Laurie et al. (2012). "A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab". Breast Cancer Research and Treatment 133 (3): 1057–65. doi:10.1007/s10549-012-2003-y. PMC 3387495. PMID 22418700. 
  13. ^ Schuler, M; Awada, A; Harter, P; Canon, JL; Possinger, K; Schmidt, M; De Grève, J; Neven, P et al. (2012). "A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer". Breast cancer research and treatment. doi:10.1007/s10549-012-2126-1. PMID 22763464. 
  14. ^ Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (German)
CI monoclonal antibodies ("-mab")
Others for solid tumors
Tyrosine-kinase inhibitors ("-nib")

EML4-ALK (Crizotinib)

RET inhibitors: Vandetanib (Also VEGFR and EGFR).

c-MET inhibitor: Cabozantinib (Also VEGFR2).
Other


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