Erlotinib

Erlotinib

Systematic (IUPAC) name
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine
Clinical data
Trade names	Tarceva
AHFS/Drugs.com	monograph
MedlinePlus	a605008
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: D (Evidence of risk)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral tablets
Pharmacokinetic data
Bioavailability	59%
Protein binding	95%
Metabolism	Hepatic (mainly CYP3A4, less CYP1A2)
Biological half-life	36.2 hrs (median)
Excretion	>98% as metabolites, of which >90% via faeces, 9% via urine
Identifiers
CAS Number	183321-74-6 Y
ATC code	L01XE03 (WHO)
PubChem	CID: 176870
IUPHAR/BPS	4920
DrugBank	DB00530 Y
ChemSpider	154044 Y
UNII	J4T82NDH7E Y
KEGG	D07907 Y
ChEBI	CHEBI:114785 Y
ChEMBL	CHEMBL553 Y
Chemical data
Formula	C22H23N3O4
Molecular mass	393.436 g/mol
SMILES COCCOc1cc2c(cc1OCCOC)ncnc2Nc3cccc(c3)C#C
InChI InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25) Y Key:AAKJLRGGTJKAMG-UHFFFAOYSA-N Y
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Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small cell lung cancer (NSCLC), 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.

Mechanism

Erlotinib is an epidermal growth factor receptor inhibitor (EGFR inhibitor). The drug follows Iressa (gefitinib), 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 EGFR molecules need to come together to form a homodimer. 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.

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 survival by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone.

The U.S. Food and Drug Administration (FDA) has approved erlotinib 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 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 in cancer patients has been developed by Genzyme.

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 May 2012, the US District Court of Delaware passed an order in favour of OSI Pharmaceutical LLC against Mylan Pharmaceuticals upholding the validity of the patent for Erlotinib. In India, generic pharmaceutical firm Cipla is battling with Roche against the Indian patent for this drug.

Side effects

Common side effects

• Rash 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."
• Diarrhea
• Loss of appetite
• Fatigue
• Rarely, interstitial pneumonitis, which is characterized by cough and increased dyspnea. 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

• gastrointestinal tract toxicity
  • serious or fatal gastrointestinal tract perforations
• skin toxicity
  • bullous, blistering, and exfoliative skin conditions (some fatal)
  • Stevens–Johnson syndrome/toxic epidermal necrolysis
• ocular disorders
  • corneal lesions
• Pulmonary toxicity
  • interstitial pneumonitis
  • bronchiolitis obliterans with organizing pneumonia (BOOP)
  • pulmonary fibrosis
  • fatal asymmetric interstitial lung disease

Interactions

As per published report, erlotinib is not a substrate for either of hepatic OATPs (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. Compounds which induce this enzyme (i.e. stimulate its production), such as St John's wort, can lower erlotinib concentrations, while inhibitors can increase concentrations.

Resistance to treatment

Erlotinib bound to ErbB1 at 2.6A resolution; surface colour indicates hydrophobicity.

As with other ATP competitive small molecule tyrosine kinase inhibitors, such as imatinib (Gleevec) 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). While proponents of the 'gatekeeper' mutation hypothesis suggest this mutation prevents the binding of erlotinib through steric hindrance, research suggests that T790M confers an increase in ATP binding affinity, thereby reducing the inhibitory efficacy of erlotinib.

Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3 dependent activation of PI3K.

Other cases of resistance can involve numerous mutations, including recruitment of a mutated IGF-1 receptor to dimerise with EGFR so forming a heterodimer. This allows activation of the downstream effectors of EGFR even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around TKIs such as AG1024 or AG538 or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541). The monoclonal antibody figitumumab which targets the IGF-1R is currently undergoing clinical trials.

Another cause of resistance can be inactivating mutations of the PTEN tumour suppressor, which allow increased activation of Akt independent of stimulation by EGFR.

The most promising approach to combating resistance is likely to be combination therapy. Commencing treatment with a number of different therapeutic agents with differing modes of action is thought to provide the best defence against development of T790M and other resistance conferring mutations.

See also

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
• FAQ: 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