Gefitinib 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.
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 a family of receptors which includes Her1(erb-B1), Her2(erb-B2), and Her 3(erb-B3). 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. 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.
FDA approved in May 2003 for NSCLC, 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.
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. As at August 2012 New Zealand has approved gefitinib as first line treatment for patients with EGFr mutation for naive locally advanced or metastatic, unresectable NSCLC. This publicly funded for an initial 4 month term and renewal if no progression.
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 to gefitinib. However, since there is, so far, little evidence that erlotinib is suitable as a first line treatment in NSCLC, it is currently restricted to patients who have previously received at least one chemotherapy regime.)
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. Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, corneal erosion, aberrant eyelash and hair growth.