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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 cat. D (US)
Legal status POM (UK) â„ž-only (US)
Routes Oral tablets
Pharmacokinetic data
Bioavailability 59%
Protein binding 95%
Metabolism Hepatic (mainly CYP3A4, less CYP1A2)
Half-life 36.2 hrs (median)
Excretion >98% as metabolites, of which >90% via faeces, 9% via urine
Identifiers
CAS number 183321-74-6 YesY
ATC code L01XE03
PubChem CID 176870
DrugBank DB00530
ChemSpider 154044 YesY
UNII J4T82NDH7E YesY
KEGG D07907 YesY
ChEBI CHEBI:114785 YesY
ChEMBL CHEMBL553 YesY
Chemical data
Formula C22H23N3O4 
Mol. mass 393.436 g/mol
SMILES eMolecules & PubChem
 YesY (what is this?)  (verify)

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.

Contents

[edit] Mechanism

Erlotinib is an 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.[1] 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.

[edit] 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.[2][3] The manufacturer estimated that erlotinib can extend life by approximately 3.3 months.[4] This is at a cost of CDN$95,000, which some researchers call "marginally" cost effective, and led NICE to refuse to recommend it.[5]

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.[6]

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.[citation needed]

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.[7]

The drug's US patent will expire in 2020.[8] 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.[9] 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.[10][11]

[edit] Side effects

[edit] 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.[12] 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."[13] 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."[14]
  • 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)

[edit] 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 Genentech 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.[15]

[edit] Interactions

Erlotinib is mainly metabolised 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.[16]

[edit] 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).[17] 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 reducing the inhibitory effect of erlotinib.[18]

Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3 dependent activation of PI3K.[19][20]

Other cases of resistance can involve numerous mutations, including recruitment of a mutated IGF-1 receptor to homodimerise with EGFR so forming a heterodimer.[21] 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[22] or pyrrolo[2,3-d]-pyrimidine derivatives such as NVP-AEW541[23]). The monoclonal antibody figitumumab which targets the IGF-1R is currently undergoing clinical trials.[24][25].

Another cause of resistance can be inactivating mutations of the PTEN tumour suppressor which allow increased activation of Akt independent of stimulation by EGFR.[26]

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.[27]

[edit] References

  1. ^ Raymond E, Faivre S, Armand J (2000). "Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy". Drugs 60 Suppl 1: 15–23; discussion 41–2. PMID 11129168. 
  2. ^ 2009 - SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC.
  3. ^ April 2010 - Tarceva Indication Announcement Letter
  4. ^ NICE unable to recommend erlotinib for the maintenance treatment of non-small-cell lung cancer
  5. ^ Erlotinib for Advanced NSCLC is "Marginally" Cost Effective, Fran Lowry, Medscape, 25 February 2010
  6. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  7. ^ Li Z, Xu M, Xing S, Ho W, Ishii T, Li Q, Fu X, Zhao Z (2007). "Erlotinib Effectively Inhibits JAK2V617F Activity and Polycythemia Vera Cell Growth". J Biol Chem 282 (6): 3428–32. doi:10.1074/jbc.C600277200. PMC 2096634. PMID 17178722. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2096634. 
  8. ^ http://drugpatentwatch.com/ultimate/preview/ingredient/index.php?query=erlotinib
  9. ^ http://sify.com/finance/equity/fullstory.php?id=14626687
  10. ^ http://sify.com/finance/equity/fullstory.php?id=14612495
  11. ^ http://www.cipla.com/whatsnew/news.htm#27apr09
  12. ^ Dudek A, Kmak K, Koopmeiners J, Keshtgarpour M (2006). "Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer". Lung Cancer 51 (1): 89–96. doi:10.1016/j.lungcan.2005.09.002. PMID 16290256. 
  13. ^ Román PĂ©rez-Soler, M.D., et al. (2004). "Selected Highlights". Lung Cancer Frontiers 22 (16): 3238–3247. 
  14. ^ Thomas L. Petty, M.D. (2003). "Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer". Journal of Clinical Oncology 1 (17): 3–4. 
  15. ^ http://jama.ama-assn.org/cgi/content/extract/301/24/2542-b
  16. ^ Haberfeld, H, ed. (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Ă–sterreichischer Apothekerverlag. 
  17. ^ Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, Chiang A, Yang G, Ouerfelli O, Kris MG, Ladanyi M, Miller VA, Pao W (2006). "Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.". Clin Cancer Res 12 (1): 6494–501. doi:10.1158/1078-0432.CCR-06-1570. PMID 17085664. 
  18. ^ Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ (2008). "The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.". PNAS 105 (6): 2070–5. doi:10.1073/pnas.0709662105. PMID 18227510. 
  19. ^ Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA (2007). "MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling.". Science 316 (5827): 1039–43. doi:10.1126/science.1141478. PMID 17463250. 
  20. ^ EBean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W (2007). "MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.". PNAS 104 (52): 20932–7. doi:10.1073/pnas.0710370104. PMID 18093943. 
  21. ^ Jones H, Goddard L, Gee J, Hiscox S, Rubini M, Barrow D, Knowlden J, Williams S, Wakeling A, Nicholson R (2004). "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells". Endocr Relat Cancer 11 (4): 793–814. doi:10.1677/erc.1.00799. PMID 15613453. http://erc.endocrinology-journals.org/cgi/content/full/11/4/793.  Free full text
  22. ^ Blum G, Gazit A, Levitzki A (2000). "Substrate competitive inhibitors of IGF-1 receptor kinase". Biochemistry 39 (51): 15705–12. doi:10.1021/bi001516y. PMID 11123895. 
  23. ^ Warshamana-Greene G, Litz J, Buchdunger E, GarcĂ­a-EcheverrĂ­a C, Hofmann F, Krystal G (2005). "The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy". Clin Cancer Res 11 (4): 1563–71. doi:10.1158/1078-0432.CCR-04-1544. PMID 15746061.  Free full text
  24. ^ ClinicalTrials.gov NCT00976508 Figitumumab Combined With Pegvisomant For Advanced Solid Tumors
  25. ^ ClinicalTrials.gov NCT00635245 CP-751871 in Treating Women With Early-Stage Breast Cancer That Can Be Removed by Surgery
  26. ^ Sos, M. L.; Koker, M.; Weir, B. A.; Heynck, S.; Rabinovsky, R.; Zander, T.; Seeger, J. M.; Weiss, J. et al (2009). "PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR". Cancer Research 69 (8): 3256–3261. doi:10.1158/0008-5472.CAN-08-4055. PMC 2849653. PMID 19351834. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2849653.  edit
  27. ^ J Clin Invest. 2009 October 1; 119(10). Tang, Dual MET EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer, Br J Cancer. 2008 September 16; 99(6).

[edit] External links
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Tyrosine-kinase inhibitors ("-nib")
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