Afatinib

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Afatinib
Afatinib2DACS.svg
Afatinib 3D ball-and-stick 4G5P.png
Clinical data
Trade names Gilotrif, Giotrif
Synonyms BIBW 2992
AHFS/Drugs.com Multum Consumer Information
License data
Pregnancy
category
  • AU: C
  • US: D (Evidence of risk)
    Routes of
    administration
    Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding 95%
    Metabolism CYP not involved
    Elimination half-life 37 hours
    Excretion Faeces (85%), urine (4%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.239.035 Blue pencil.svg
    Chemical and physical data
    Formula C24H25ClFN5O3
    Molar mass 485.937 g/mol
    3D model (JSmol)
     X mark.svgNYes check.svgY  (what is this?)    (verify)

    Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). [1] [2] [3] It belongs to the tyrosine kinase inhibitor family of medications. [4] It is taken by mouth. [4]

    Contents

    It is mainly used to treat cases of NSCLC that harbour mutations in the epidermal growth factor receptor (EGFR) gene. [5]

    Epidermal growth factor receptor protein-coding gene in the species Homo sapiens

    The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

    Medical uses

    It has received regulatory approval for use as a treatment for non-small cell lung cancer, [6] [4] [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: [6] [4] [7] [8] [10]

    Very common (>10% frequency)
    Stomatitis inflammation of the mouth and lips

    Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration.

    Paronychia nail disease that is an often-tender bacterial or fungal infection of the hand or foot where the nail and skin meet at the side or the base of a finger or toenail

    Paronychia is a nail disease that is an often-tender bacterial or fungal infection of the hand or foot where the nail and skin meet at the side or the base of a finger or toenail. The infection can start suddenly or gradually. Paronychia is commonly misapplied as a synonym for whitlow or felon. The term is from Greek: παρωνυχία from para, "around", onyx, "nail" and the abstract noun suffix -ia.

    Common (1–10% frequency)

    Dysgeusia, also known as parageusia, is a distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is a decrease in taste sensitivity. An alteration in taste or smell may be a secondary process in various disease states, or it may be the primary symptom. The distortion in the sense of taste is the only symptom, and diagnosis is usually complicated since the sense of taste is tied together with other sensory systems. Common causes of dysgeusia include chemotherapy, asthma treatment with albuterol, and zinc deficiency. Different drugs could also be responsible for altering taste and resulting in dysgeusia. Due to the variety of causes of dysgeusia, there are many possible treatments that are effective in alleviating or terminating the symptoms of dysgeusia. These include artificial saliva, pilocarpine, zinc supplementation, alterations in drug therapy, and alpha lipoic acid.

    Cheilitis inflammation of the lips

    Cheilitis is inflammation of the lips. This inflammation may include the perioral skin, the vermilion border, or the labial mucosa. The skin and the vermilion border are more commonly involved, as the mucosa is less affected by inflammatory and allergic reactions.

    Conjunctivitis inflammation of the outermost layer of the eye and the inner surface of the eyelids

    Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The affected eye may have increased tears or be "stuck shut" in the morning. Swelling of the white part of the eye may also occur. Itching is more common in cases due to allergies. Conjunctivitis can affect one or both eyes.

    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 tyrosine-kinase inhibitors (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. [2]

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

    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] It also shows strong activity against exon 18 mutations (particularly G719) and is currently the preferred EGFR-TKI therapy for exon 18 mutations (particularly G719x). [17] [ verification needed ]

    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. [18]

    Related Research Articles

    Tyrosine kinase enzyme that can add a phosphate group from ATP to a cellular protein

    A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases are a subclass of protein kinase.

    Gefitinib chemical compound

    Gefitinib (ZD1839) is a drug used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR. It is marketed by AstraZeneca and Teva.

    Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid that is soluble in water. Also known as 1,3-diazanaphthalene, quinazoline received its name from being an aza derivative of quinoline. Though the parent quinazoline molecule is rarely mentioned by itself in technical literature, substituted derivatives have been synthesized for medicinal purposes such as antimalarial and anticancer agents. Quinazoline is a planar molecule. It is isomeric with the other diazanaphthalenes of the benzodiazine subgroup: cinnoline, quinoxaline, and phthalazine.

    Erlotinib chemical compound

    Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).

    Targeted therapy

    Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

    Lapatinib chemical compound

    Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

    Matuzumab is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was derived was developed at the Wistar Institute in Philadelphia, Pennsylvania

    Combined small-cell lung carcinoma

    Combined small cell lung carcinoma is a form of multiphasic lung cancer that is diagnosed by a pathologist when a malignant tumor arising from transformed cells originating in lung tissue contains a component of small cell lung carcinoma (SCLC) admixed with one components of non-small cell lung carcinoma (NSCLC).

    Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.

    Tyrosine-kinase inhibitor

    A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit. TKIs are typically used as anticancer drugs. For example, they have substantially improved outcomes in chronic myelogenous leukemia.

    Angiokinase inhibitors are a new therapeutic target for the management of cancer. They inhibit tumour angiogenesis, one of the key processes leading to invasion and metastasis of solid tumours, by targeting receptor tyrosine kinases. Examples include nintedanib, afatinib and motesanib.

    Brigatinib chemical compound

    Brigatinib is a small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals, Inc. Brigatinib acts as both a anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

    Growth factor receptor inhibitors are drugs that target the growth factor receptors of cells. They interfere with binding of the growth factor to the corresponding growth factor receptors, impeding cell growth and are used medically to treat cancer.

    Icotinib chemical compound

    Icotinib is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Icotinib is approved for use as first-line monotherapy in patients with non-small-cell lung cancer with somatic EGFR mutations. Currently, it is solely approved and marketed in China.

    Osimertinib chemical compound

    Osimertinib is a medication used to treat non-small-cell lung carcinomas with a specific mutation. 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.

    T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinase domain. Threonine is a small polar amino acid; methionine is a larger nonpolar amino acid.

    Buparlisib

    Buparlisib is an investigational small molecule orally-available pan-class I phosphoinositide 3-kinase inhibitor.

    Abemaciclib CDK inhibitor

    Abemaciclib is a drug for the treatment of advanced or metastatic breast cancers. It was developed by Eli Lilly and it acts as a CDK inhibitor selective for CDK4 and CDK6.

    Olmutinib chemical compound

    Olmutinib (INN) is an investigational anti-cancer drug. It acts by covalently bonding to a cysteine residue near the kinase domain of epidermal growth factor receptor (EGFR).

    References

    1. H. Spreitzer (13 May 2008). "Neue Wirkstoffe – Tovok". Österreichische Apothekerzeitung (in German) (10/2008): 498.
    2. 1 2 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.
    3. "Afatinib". US Food and Drug Administration. 12 July 2013.
    4. 1 2 3 4 "GIOTRIF® Afatinib (as afatinib dimaleate)" (PDF). TGA eBusiness Services. Boehringer Ingelheim Pty Limited. 7 November 2013. Retrieved 28 January 2014.
    5. Vavalà, T (2017). "Role of afatinib in the treatment of advanced lung squamous cell carcinoma". Clinical Pharmacology: Advances and Applications. 9: 147–157. doi:10.2147/CPAA.S112715. PMC   5709991 . PMID   29225480.
    6. 1 2 "GILOTRIF (afatinib) tablet, film coated [Boehringer Ingelheim Pharmaceuticals, Inc.]". DailyMed. Boehringer Ingelheim Pharmaceuticals, Inc. November 2013. Retrieved 28 January 2014.
    7. 1 2 "Giotrif 20 mg film-coated tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Boehringer Ingelheim Limited. 20 January 2014. Retrieved 28 January 2014.
    8. 1 2 "Giotrif : EPAR -Product Information" (PDF). European Medicines Agency. Boehringer Ingelheim International GmbH. 16 October 2013. Retrieved 28 January 2014.
    9. 1 2 Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, Munster P, Frakes L, Kelly S, Garcia AA, Cleator S, Uttenreuther-Fischer M, Jones H, Wind S, Vinisko R, Hickish T (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.
    10. "Gilotrif (afatinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 January 2014.
    11. Li (2008). "BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models". Oncogene. 27 (34): 4702–4711. doi:10.1038/onc.2008.109. PMC   2748240 . PMID   18408761.
    12. Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Frühjahr 2013. (in 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. "Afatinib (BIBW 2992*) Triples Progression Free Survival in Phase III Study in Lung Cancer Patients". BusinessWire. 11 October 2010.
    15. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC (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.
    16. Yang, JC; Wu, YL; Schuler, M; Sebastian, M; Popat, S; Yamamoto, N; Zhou, C; Hu, CP; O'Byrne, K; Feng, J; Lu, S; Huang, Y; Geater, SL; Lee, KY; Tsai, CM; Gorbunova, V; Hirsh, V; Bennouna, J; Orlov, S; Mok, T; Boyer, M; Su, WC; Lee, KH; Kato, T; Massey, D; Shahidi, M; Zazulina, V; Sequist, LV (February 2015). "Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials". The Lancet Oncology. 16 (2): 141–51. doi:10.1016/s1470-2045(14)71173-8. PMID   25589191.
    17. Kobayashi, Y (2015). "EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs". Clin Cancer Res. 21 (23): 5305–13. doi:10.1158/1078-0432.CCR-15-1046. PMID   26206867.
    18. Schuler M, Awada A, Harter P, Canon JL, Possinger K, Schmidt M, De Grève J, Neven P, Dirix L, Jonat W, Beckmann MW, Schütte J, Fasching PA, Gottschalk N, Besse-Hammer T, Fleischer F, Wind S, Uttenreuther-Fischer M, Piccart M, Harbeck N (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. 134 (3): 1149–59. doi:10.1007/s10549-012-2126-1. PMC   3409367 . PMID   22763464.