Article: Gefitinib

Gefitinib
Systematic (IUPAC) name
N-(3-chloro-4-fluoro-phenyl)-7-methoxy- 6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
Identifiers
CAS number	184475-35-2
ATC code	L01XX31
PubChem	123631
DrugBank	APRD00997
Chemical data
Formula	C22H24N4ClFO3
Mol. weight	446.902 g/mol
Pharmacokinetic data
Bioavailability	59% (oral)
Protein binding	90%
Metabolism	Hepatic (mainly CYP3A4)
Half life	6–49 hours
Excretion	Faecal
Therapeutic considerations
Pregnancy cat.	C (Au), D (U.S.)
Legal status	S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral

Gefitinib (INN) (IPA: [gɛˈfɪtənɪb]) is a drug used in the treatment of certain types of cancer. Acting in a similar manner to erlotinib (marketed as Tarceva), gefitinib selectively targets the mutant proteins in malignant cells. It is marketed by AstraZeneca under the trade name Iressa.

Mechanism of action

Gefitinib is the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain. 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 apoptotic Ras signal transduction 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 Ras signal transduction cascade is inhibited, and malignant cells are inhibited.

Clinical uses

Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy.

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

In 2004, AstraZeneca informed the United States Food and Drug Administration (FDA) that a large randomized study [1] failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC). Whether progression-free survival is prolonged is not clear from this statement. AstraZeneca also withdrew their application to market gefitinib in Europe shortly after this announcement.

Erlotinib is another EGFR tyrosine kinase inhibitor that works in the same way as gefitinib. Given the lack of survival advantage for gefitinib and the positive results for erlotinib, erlotinib has replaced gefitinib in the United States (except in patients where gefitinib has had a proven response).

Genzyme test

On September 26 2005, Genzyme Corp. announced that it would market a test to detect EGFR expression, designed to help predict which lung cancer patients may respond best to some therapies, including gefitinib and erlotinib. This method is used to identify ahead of time which patients may respond to medications in this drug class.

The test, expected to cost about $975, examines the genetics of tumors removed for biopsy for mutations that make them susceptible to treatment.

The EGFR expression test may also help Genentech and 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. This led the Food and Drug Administration this summer to partially withdraw the drug in the U.S., no longer allowing its prescription for new patients. The drug remains on the market in Europe. In the U.S., erlotinib has essentially replaced gefitinib (except in patients where gefitinib has had a proven response).

Adverse effects

As gefitinib is a selective chemotherapeutic agent, its tolerability profile is far superior to previous cytotoxic agents. Adverse drug reactions (ADRs) do still occur however, but may be preferable to the fatal consequences of not taking the therapy.

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.^[3]

Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, corneal erosion, aberrant eyelash and hair growth.^[3]