Gefitinib
Encyclopedia
Gefitinib INN
(icon), trade name Iressa, is a drug
used in the treatment of certain types of cancer
, particularly those with mutated and overactive EGFR
. Gefitinib is an EGFR inhibitor, like erlotinib
, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. It is marketed by AstraZeneca
and Teva
.
'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 carcinoma
s - 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.
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.
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. ))
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.
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.
s (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
.
Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, cornea
l erosion, aberrant eyelash and hair growth.
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]
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
(icon), trade name Iressa, is a drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used in the treatment of certain types of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, particularly those with mutated and overactive EGFR
EGFR
EGFR is a four letter abbreviation that may refer to:* Epidermal growth factor receptor * Estimated glomerular filtration rate...
. Gefitinib is an EGFR inhibitor, like erlotinib
Erlotinib
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. It is marketed by AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
and Teva
Teva
Companies commonly known as Teva include:*Teva Pharmaceutical Industries, Ltd.*Teva Naot*Teva sport sandals*Teva Learning Center...
.
Mechanism of action
Gefitinib is the first selective inhibitor of epidermal growth factor receptorEpidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
's (EGFR) tyrosine kinase
Tyrosine kinase
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....
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 carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
s - for example in lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic Ras signalling cascade
Anti-apoptotic Ras signalling cascade
The Anti-apoptotic Ras signalling cascade is an intracellular signal transduction cascadethat involves the Ras protein and inhibits apoptosis...
, 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
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
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
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the anti-apoptotic Ras signal transduction cascade
Anti-apoptotic Ras signalling cascade
The Anti-apoptotic Ras signalling cascade is an intracellular signal transduction cascadethat involves the Ras protein and inhibits apoptosis...
is inhibited, and malignant cells are inhibited.
Clinical uses
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.
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
Erlotinib
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
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.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 far superior to previous cytotoxic agents. Adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (ADRs) do still occur however, but may be preferable to the fatal consequences of not taking the therapy.
Acne
Acne vulgaris
Acne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
is reported very commonly. Other common adverse effects (≥1% of patients) include: diarrhoea, nausea, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, stomatitis
Stomatitis
Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth...
, dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, skin reactions, paronychia
Paronychia
The nail disease paronychia , commonly misidentified as a synonym for whitlow or felon, is an often-tender bacterial or fungal hand infection or foot infection where the nail and skin meet at the side or the base of a finger or toenail...
, asymptomatic elevations of liver enzymes, asthenia, conjunctivitis
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...
, blepharitis
Blepharitis
Blepharitis is an ocular condition characterized by chronic inflammation of the eyelid, the severity and time course of which can vary. Onset can be acute, resolving without treatment within 2–4 weeks , but more generally is a long standing inflammation varying in severity...
.
Infrequent adverse effects (0.1–1% of patients) include: interstitial lung disease, cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
l erosion, aberrant eyelash and hair growth.
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
- ErlotinibErlotinibErlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor . It is marketed in the United States by Genentech and OSI...
, another EGFR tyrosine kinase inhibitor that has a similar mechanism of action to gefitinib - Personalized medicinePersonalized medicinePersonalized medicine is a medical model emphasizing in general the customization of healthcare, with all decisions and practices being tailored to individual patients in whatever ways possible...