Erlotinib, sold under the brand name Tarceva among others, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

non-small cell lung cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

(NSCLC) and

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...

. Specifically it is used for NSCLC with mutations in the

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...

(EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Common side effects include rash, diarrhea, muscle pain, joint pain, and cough. Serious side effects may include lung problems,

kidney problems Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...

gastrointestinal perforation Gastrointestinal perforation, also known as gastrointestinal rupture, is a hole in the wall of the gastrointestinal tract. The gastrointestinal tract is composed of hollow digestive organs leading from the mouth to the anus. Symptoms of gastroi ...

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

, and

corneal ulceration Corneal ulcer, often resulting from keratitis is an inflammatory or, more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans parti ...

. Use in

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

may harm the baby. It is a receptor

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

, which acts on the

(EGFR). Erlotinib was approved for medical use in the United States in 2004. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

Medical uses

Lung cancer

Erlotinib in unresectable non-small cell lung cancer when added to chemotherapy improves

overall survival Survival rate is a part of survival analysis. It is the proportion of people in a study or treatment group still alive at a given period of time after diagnosis. It is a method of describing prognosis in certain disease conditions, and can be use ...

by 19%, and improved

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is ...

(PFS) by 29%, when compared to chemotherapy alone. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) approved erlotinib for the treatment of locally advanced or

metastatic Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

that has failed at least one prior

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

regimen. In lung cancer, erlotinib has been shown to be effective in patients with or without EGFR mutations, but appears to be more effective in patients with EGFR mutations. Overall survival, progression-free survival and one-year survival are similar to standard second-line therapy (docetaxel or pemetrexed). Overall response rate is about 50% better than standard second-line chemotherapy. 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. A test for the EGFR mutation has been developed by

Genzyme Genzyme (also known as Genzyme Transgenics Corp or GTC Biotherapeutics) was an American biotechnology company based in Cambridge, Massachusetts. From its acquisition in 2011 to 2022 Genzyme operated as a fully owned subsidiary of Sanofi. In 2010, ...

Pancreatic cancer

In November 2005, the FDA approved erlotinib in combination with

gemcitabine Gemcitabine, sold under the brand name Gemzar, among others, is a chemotherapy medication used to treat cancers. It is used to treat testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder ca ...

for treatment of locally advanced, unresectable, or metastatic

Resistance to treatment

As with other ATP competitive small molecule tyrosine kinase inhibitors, such as

imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...

in CML, patients rapidly develop resistance. In the case of erlotinib this typically occurs 8–12 months from the start of treatment. Over 50% of resistance is caused by a mutation in the ATP binding pocket of the EGFR kinase domain involving substitution of a small polar threonine residue with a large nonpolar methionine residue (

T790M T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR kinas ...

). Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives

ERBB3 Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ''ERBB3'' gene. ErbB3 is a member of the EGFR family, epidermal growth factor re ...

dependent activation of

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

Side effects

Common

Rash A rash is a change of the skin that 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, cracke ...

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. 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

kin Kin usually refers to kinship and family. Kin or KIN may also refer to: Places * Kin empires and dynasties of China, now romanized as ''Jin'' *Kin, Okinawa, a town in Okinawa, Japan * Kin, Pakistan, a village along the Indus in Pakistan * Kin ...

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

ashes Ashes may refer to: * Ash, the solid remnants of fires. Media and entertainment Art * ''Ashes'' (Munch), an 1894 painting by Edvard Munch Film * ''The Ashes'' (film), a 1965 Polish film by director Andrzej Wajda * ''Ashes'' (1922 film), ...

have a far better survival, than those with only mild reactions and much better than those with no cutaneous manifestations of drug effects." *

Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

* Loss of appetite *

Fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

* Partial hair loss (by strands, not typically in clumps)

Rare

* interstitial

pneumonitis Pneumonitis describes general inflammation of lung tissue. Possible causative agents include radiation therapy of the chest, exposure to medications used during chemo-therapy, the inhalation of debris (e.g., animal dander), aspiration, herbicide ...

, which is characterized by cough and increased

dyspnea Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that ...

. This may be severe and must be considered among those patients whose breathing acutely worsens. * ingrown hairs, such as eyelashes * gastrointestinal tract toxicity ** serious or fatal gastrointestinal tract perforations * skin toxicity ** bullous, blistering, and exfoliative skin conditions (some fatal) **

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and #Classification, Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN) overlap, they are considered febrile mucocutaneous d ...

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and f ...

* ocular disorders ** corneal lesions * Pulmonary toxicity **

interstitial pneumonitis Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the Pulmonary alveolus, alveoli (air sacs) of the lungs. It concerns Pulmonar ...

** bronchiolitis obliterans with organizing pneumonia (BOOP) **

pulmonary fibrosis Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory ...

** fatal asymmetric

interstitial lung disease Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs. It concerns alveolar epithelium, pulm ...

Interactions

Erlotinib is not a substrate for either of hepatic

OATP Members of the Organic Anion Transporter (OAT) Family (organic-anion-transporting polypeptides, OATP) are membrane transport proteins or 'transporters' that mediate the transport of mainly organic anions across the cell membrane. Therefore, OATPs ...

s (OATP1B1 or OATP1B3). Also, erlotinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter. Erlotinib is mainly metabolized by the liver enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. Compounds which induce this enzyme (i.e. stimulate its production), such as

St John's wort ''Hypericum perforatum'', commonly known as St. John's wort (sometimes perforate St. John's wort or common St. John's wort), is a flowering plant in the family Hypericaceae. It is a hairless, perennial herb with woody roots, yellow flowers ma ...

, can lower erlotinib concentrations, while inhibitors can increase concentrations.

Mechanism

Erlotinib is an epidermal growth factor receptor inhibitor (

EGFR inhibitor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...

). The drug follows Iressa (

gefitinib Gefitinib, sold under the brand name Iressa, is a medication 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 targe ...

), which was the first drug of this type. Erlotinib specifically targets the

(EGFR)

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

, which is highly expressed and occasionally

mutated In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral rep ...

in various forms of cancer. It binds in a reversible fashion to the

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP) binding site of the receptor. For the signal to be transmitted, two EGFR molecules need to come together to form a

homodimer In biochemistry, a protein dimer is a macromolecular complex or protein multimer, multimer formed by two protein monomers, or single proteins, which are usually Non-covalent interaction, non-covalently bound. Many macromolecules, such as proteins ...

. These then use the molecule of ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. When erlotinib binds to EGFR, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.

Society and culture

It is marketed in the United States by

Genentech Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It operates as an independent subsidiary of holding company Roche. Genentech Research and Early Development operates as an independent cent ...

and

OSI Pharmaceuticals OSI Pharmaceuticals, Inc. was an American pharmaceutical company formerly based in Long Island, New York with facilities in Colorado, New Jersey and the United Kingdom. On Sunday, May 16, 2010 OSI agreed to be acquired by Japan-based, TSE-liste ...

and elsewhere by

Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Switzerland, Swiss multinational corporation, multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, ...

. The drug's U.S. patent expired in 2020. In May 2012, the US District Court of Delaware passed an order in favor of OSI Pharmaceutical LLC against Mylan Pharmaceuticals upholding the validity of the patent for Erlotinib. In India, generic pharmaceutical firm

Cipla Cipla Limited is an Indian multinational pharmaceutical company headquartered in Mumbai. Cipla primarily focuses on developing medication to treat respiratory disease, cardiovascular disease, arthritis, diabetes, depression, paediatric and var ...

is battling with Roche against the Indian patent for this drug.

References

External links

* {{Portal bar, Medicine Secondary amines Astellas Pharma Ethers Drugs developed by Hoffmann-La Roche Drugs developed by Genentech Phenol ethers Phenyl compounds Alkyne derivatives Quinazolines Receptor tyrosine kinase inhibitors World Health Organization essential medicines Wikipedia medicine articles ready to translate Orphan drugs