Erlotinib
Encyclopedia
Erlotinib hydrochloride (trade name Tarceva) 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
(EGFR). It is marketed in the United States
by Genentech
and OSI Pharmaceuticals
and elsewhere by Roche. In lung cancer, it extends life by an average of 3.3 months at a cost of CDN$95,000.
, which was the first drug of this type. Erlotinib specifically targets the epidermal growth factor receptor
(EGFR) tyrosine kinase
, which is highly expressed and occasionally mutated
in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate
(ATP) binding site of the receptor. For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change
in their intracellular structure, exposing a further binding site for binding proteins that cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped.
by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone. The manufacturer estimated that erlotinib can extend life by approximately 3.3 months. This is at a cost of CDN$95,000, which some researchers call "marginally" cost effective, and led NICE
to refuse to recommend it.
The U.S. Food and Drug Administration (FDA) has approved for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy
regimen.
In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer
.
In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in the group of patients with EGFR mutations. A test for the EGFR mutation in cancer patients has been developed by Genzyme
. The response rate among EGFR mutation positive patients is approximately 60%. Patients who are non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC are more likely to have EGFR mutations, but mutations can occur in all types of patients.
EGFR positive patients are generally KRAS
negative.
Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera
(PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.
The drug's US patent will expire in 2020.
In India, generic pharmaceutical firm Cipla
is battling with Roche against the Indian patent for this drug. In April 2009, the Delhi High Court granted a final approval to Cipla to manufacture and sell its generic version of Erlotinib in India. Meanwhile, another generic pharmaceutical firm - Natco is also seeking to manufacture the generic version of Erlotinib in India but sell it to patients in Nepal using the TRIPS Agreements' Doha Declaration.
and OSI Pharmaceuticals
, some people prescribed erlotinib have developed serious or fatal gastrointestinal tract perforations; "bullous, blistering, and exfoliative skin conditions, some fatal; and serious eye problems such as corneal lesions. Some of the cases, including ones which resulted in death, were suggestive of Stevens–Johnson syndrome/toxic epidermal necrolysis.
. Activators of this enzyme, such as St John's wort
, can lower erlotinib concentrations, while inhibitors can increase concentrations.
Chemically resistance appears to occur by recruiting a mutated IGF-1 receptor
to act as one of the EGFR partners in the homodimer, so forming a heterodimer. This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538 or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541).
Pan-inhibitors show some promise in combating resistance, at least in cell studies. Today (3/10) the most promising approach to combating resistance appears to be a dual approach, combining pan-inhibitors like HKI 272 with Erbitux. "Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab (Erbitux) and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance." Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
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 to treat non-small cell lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor
Epidermal 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...
(EGFR). It is marketed in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
by Genentech
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
and OSI Pharmaceuticals
OSI Pharmaceuticals
OSI Pharmaceuticals, Inc. is an American pharmaceutical company based in Long Island, New York with facilities in Colorado, New Jersey and the United Kingdom. OSI specializes in the discovery and development of molecular targeted therapies, and was listed in the NASDAQ Biotechnology Index...
and elsewhere by Roche. In lung cancer, it extends life by an average of 3.3 months at a cost of CDN$95,000.
Mechanism
Erlotinib is an EGFR inhibitor. The drug follows Iressa gefitinibGefitinib
Gefitinib INN , 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 in target cells...
, which was the first drug of this type. Erlotinib specifically targets the epidermal growth factor receptor
Epidermal 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...
(EGFR) tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
, which is highly expressed and occasionally mutated
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in various forms of cancer. It binds in a reversible fashion 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 receptor. For the signal to be transmitted, two members of the EGFR family need to come together to form a homodimer. These then use the molecule of ATP to autophosphorylate each other, which causes a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
in their intracellular structure, exposing a further binding site for binding proteins that cause a signal cascade to the nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stopped.
Clinical applications
Erlotinib has shown a survival benefit in the treatment of lung cancer in phase III trials. The SATURN (Sequential Tarceva in Unresectable NSCLC) study found that erlotinib added to chemotherapy improved overall survivalSurvival rate
In biostatistics, survival rate is a part of survival analysis, indicating the percentage of people in a study or treatment group who are alive for a given period of time after diagnosis...
by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone. The manufacturer estimated that erlotinib can extend life by approximately 3.3 months. This is at a cost of CDN$95,000, which some researchers call "marginally" cost effective, and led NICE
NICE
NICE may refer to:* National Independent Cadres and Elites in Iraq* National Institute for Coordinated Experiments, a fictional organisation in C.S...
to refuse to recommend it.
The U.S. Food and Drug Administration (FDA) has approved for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
regimen.
In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
.
In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in the group of patients with EGFR mutations. A test for the EGFR mutation in cancer patients has been developed by Genzyme
Genzyme
Genzyme Corporation is a fully owned subsidiary of Sanofi-Aventis. Before its acquisition, Genzyme was an American biotechnology company based in Cambridge, Massachusetts. In 2010, Genzyme was the world’s third-largest biotechnology company, employing more than 11,000 people around the world...
. The response rate among EGFR mutation positive patients is approximately 60%. Patients who are non-smokers, and light former smokers, with adenocarcinoma or subtypes like BAC are more likely to have EGFR mutations, but mutations can occur in all types of patients.
EGFR positive patients are generally KRAS
KRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
negative.
Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera
Polycythemia vera
Polycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
(PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.
The drug's US patent will expire in 2020.
In India, generic pharmaceutical firm Cipla
Cipla
Cipla Limited is a prominent Indian pharmaceutical company, best-known outside its home country for manufacturing low-cost anti-AIDS drugs for HIV-positive patients in developing countries...
is battling with Roche against the Indian patent for this drug. In April 2009, the Delhi High Court granted a final approval to Cipla to manufacture and sell its generic version of Erlotinib in India. Meanwhile, another generic pharmaceutical firm - Natco is also seeking to manufacture the generic version of Erlotinib in India but sell it to patients in Nepal using the TRIPS Agreements' Doha Declaration.
Common side effects
- RashRashA rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
occurs in the majority of patients. This resembles acne and primarily involves the face and neck. It is self-limited and resolves in the majority of cases, even with continued use. Interestingly, some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed. The Journal of Clinical Oncology reported in 2004 that "cutaneous [skin] rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies." The newsletter Lung Cancer Frontiers reported in its October 2003 issue, "Patients with moderate to severe cutaneous reactions [rashes] have a far better survival, than those with only mild reactions and much better than those with no cutaneous manifestations of drug effects." - DiarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- Loss of appetite
- FatigueFatigue (physical)Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
- Rarely, interstitial pneumonitisPneumonitisPneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue.Pneumonia is pneumonitis combined with consolidation and exudation...
, which is characterized by cough and increased dyspneaDyspneaDyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
. This may be severe and must be considered among those patients whose breathing acutely worsens. - Rarely, ingrown hairs, such as eyelashes
- It has also been suggested that erlotinib can cause hearing loss.
- Partial hair loss (by strands, not typically in clumps)
Rare side effects
In spring 2009, the US Food and Drug Administration issued a warning on erlotinib. The FDA reported serious gastrointestinal tract, skin, and ocular disorders in patients taking the drug. In addition, according to a letter released by GenentechGenentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
and OSI Pharmaceuticals
OSI Pharmaceuticals
OSI Pharmaceuticals, Inc. is an American pharmaceutical company based in Long Island, New York with facilities in Colorado, New Jersey and the United Kingdom. OSI specializes in the discovery and development of molecular targeted therapies, and was listed in the NASDAQ Biotechnology Index...
, some people prescribed erlotinib have developed serious or fatal gastrointestinal tract perforations; "bullous, blistering, and exfoliative skin conditions, some fatal; and serious eye problems such as corneal lesions. Some of the cases, including ones which resulted in death, were suggestive of Stevens–Johnson syndrome/toxic epidermal necrolysis.
Interactions
Erlotinib is mainly metabolised by the liver enzyme CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Activators of this enzyme, such as St John's wort
St John's wort
St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
, can lower erlotinib concentrations, while inhibitors can increase concentrations.
Resistance to treatment
A key issue with EGFR-directed treatments is that after a period of time, frequently 8–12 months, the cancer cells become resistant to the treatment. The primary source of resistance is a second mutation called T790M. A second source of resistance is the MET mutation.Chemically resistance appears to occur by recruiting a mutated IGF-1 receptor
IGF-1 Receptor
The Insulin-like Growth Factor 1 Receptor is a transmembrane receptor that is activated by IGF-1 and by the related growth factor IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in...
to act as one of the EGFR partners in the homodimer, so forming a heterodimer. This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538 or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541).
Pan-inhibitors show some promise in combating resistance, at least in cell studies. Today (3/10) the most promising approach to combating resistance appears to be a dual approach, combining pan-inhibitors like HKI 272 with Erbitux. "Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab (Erbitux) and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance." Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
External links
- Official Tarceva website
- Tarceva Discussion Group for Cancer Patients.
- Genzyme "Genzyme Launches Exclusive Lung Cancer Test" Press Release September 27, 2005
- "Determinants of Tumor Response and Survival With Erlotinib in Patients With Non-Small-Cell Lung Cancer, Journal of Clinical Oncology, August 15, 2004.
- October 2003 issue of Lung Cancer Frontiers on rash/effectiveness correlation
- I started an EGFR inhibitor two weeks ago but haven’t developed a rash. Does this mean it’s not working?, Dr. Howard L. (Jack) West, M.D., GRACE, February 21, 2011 (directed toward the layperson).
- http://www.cancer.gov/clinicaltrials/results/lung-and-erlotinib0604l
- http://www.roche.com/med-cor-2007-10-22
- http://www.roche.com/med-cor-2009-05-30b
- http://www.cipla.com/whatsnew/news.htm#27apr09
- http://www.cipla.com/whatsnew/news.htm#20mar08