Gefitinib

Gefitinib
Systematic (IUPAC) name
N-(3-chloro-4-fluoro-phenyl)-7-methoxy-
6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
Clinical data
Trade names Iressa
AHFS/Drugs.com monograph
MedlinePlus a607002
Pregnancy cat. C (Au), D (U.S.)
Legal status S4 (Au), POM (UK), ℞-only (U.S.)
Routes Oral
Pharmacokinetic data
Bioavailability 59% (oral)
Protein binding 90%
Metabolism Hepatic (mainly CYP3A4)
Half-life 6–49 hours
Excretion Faecal
Identifiers
CAS number 184475-35-2 Y
ATC code L01XE02
PubChem CID 123631
DrugBank APRD00997
ChemSpider 110217 Y
UNII S65743JHBS Y
KEGG D01977 Y
ChEBI CHEBI:49668 Y
ChEMBL CHEMBL939 Y
Chemical data
Formula C22H24ClFN4O3 
Mol. mass 446.902 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Gefitinib INN ( /ɡɛˈfɪtɨnɪb/), (Iressa (AstraZeneca and Teva), 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.

Contents

Mechanism of action

Gefitinib is the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain. Thus gefitinib is an EGFR inhibitor. The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature source.

EGFR is overexpressed in the cells of certain types of human carcinomas - for example in lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic Ras signalling cascade, eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive non-small cell lung cancers has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.[1][2] These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, adenocarcinoma is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma).

Gefitinib inhibits EGFR tyrosine kinase by binding to the adenosine triphosphate (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the anti-apoptotic Ras signal transduction cascade is inhibited, and malignant cells are inhibited.[3]

Clinical uses

FDA approved in May 2003 for NSCLC[4], Gefitinib is currently marketed in over 64 countries.

In June 2005 the FDA withdrew approval for use in new patients due to lack of evidence that it extended life.[5]

In Europe gefitinib is indicated since 2009 in advanced NSCLC in all lines of treatment for patients harbouring EGFR mutations. This label was granted after gefitinib demonstrated as a first line treatment to significantly improve progression-free survival vs. a platinum doublet regime in patients harbouring such mutations. IPASS has been the first of four phase III trials to have confirmed gefitinib superiority in this patient population.

In most of the other countries where gefitinib is currently marketed it is approved for patients with advanced NSCLC who had received at least one previous chemotherapy regime. However, applications to expand its label as a first line treatment in patients harbouring EGFR mutations is currently in process based on the latest scientific evidence.

While gefitinib has yet to be proven to be effective in other cancers, there is potential for its use in the treatment of other cancers where EGFR overexpression is involved.

(( Erlotinib is another EGFR tyrosine kinase inhibitor that has a similar mechanism of action than gefitinib. However, since there is so far little evidence of erlotinib as a first line treatment in NSCLC, its label is currently restricted to patients who have at least received one previous chemotherapy regime. ))

Studies

IPASS (IRESSA Pan-Asia Study) was a randomized, large-scale, double-blinded study which compared gefitinib vs. carboplatin/ paclitaxel as a first line treatment in NSCLC.[6] IPASS studied 1,217 patients with confirmed adenocarnicoma histology which were former or never smokers. A pre-planned sub-group analyses showed that progression-free survival (PFS) was significantly longer for IRESSA than chemotherapy in patients with EGFR mutation positive tumours (HR 0.48, 95 per cent CI 0.36 to 0.64, p less than 0.0001), and significantly longer for chemotherapy than IRESSA in patients with EGFR mutation negative tumours (HR 2.85, 95 per cent CI 2.05 to 3.98, p less than 0.0001). This, in 2009, was the first time a targeted monotherapy has demonstrated significantly longer PFS than doublet chemotherapy.

EGFR Diagnostic tests

Genzyme, QIAGEN & other companies make tests to detect EGFR mutations, designed to help predict which lung cancer patients may respond best to some therapies, including gefitinib and erlotinib.

The tests examine the genetics of tumors removed for biopsy for mutations that make them susceptible to treatment.

The EGFR mutation test may also help AstraZeneca win regulatory approval for use of their drugs as initial therapies. Currently the TK inhibitors are approved for use only after other drugs fail. In the case of gefitinib, the drug works only in about 10% of patients with advanced non-small cell lung cancer, the most common type of lung cancer.

Adverse effects

As gefitinib is a selective chemotherapeutic agent, its tolerability profile is better than previous cytotoxic agents. Adverse drug reactions (ADRs) are acceptable for a potentially fatal disease.

Acne is reported very commonly. Other common adverse effects (≥1% of patients) include: diarrhoea, nausea, vomiting, anorexia, stomatitis, dehydration, skin reactions, paronychia, asymptomatic elevations of liver enzymes, asthenia, conjunctivitis, blepharitis.[7]

Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, corneal erosion, aberrant eyelash and hair growth.[7]

Iressa was approved and marketed from July 2002 in Japan, making it the first country to import the drug. Over 800 people have died due to Iressa’s side effects, according to the Health, Labor and Welfare Ministry. [kyodo news 2011 Jan 8]

See also

References

  1. ^ Pao W, Miller V, Zakowski M, et al. (September 2004). "EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib". Proceedings of the National Academy of Sciences of the United States of America 101 (36): 13306–11. doi:10.1073/pnas.0405220101. PMC 516528. PMID 15329413. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=516528. Retrieved 2009-07-02. 
  2. ^ Sordella R, Bell DW, Haber DA, Settleman J (August 2004). "Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways". Science 305 (5687): 1163–7. doi:10.1126/science.1101637. PMID 15284455. 
  3. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  4. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021399lbl.pdf
  5. ^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm110473.htm
  6. ^ Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Eng J Med 2009; 361. 10.1056/NEJMoa0810699.
  7. ^ a b Rossi S, editor. Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook; 2004. ISBN 0-9578521-4-2.
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