Chemistry:Erlotinib

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Short description: EGFR inhibitor for treatment of non-small-cell lung cancer
Erlotinib
Erlotinib.svg
Erlotinib-1m17-3D-balls.png
Clinical data
Trade namesTarceva
Other namesErlotinib hydrochloride
AHFS/Drugs.comMonograph
MedlinePlusa605008
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability59%
Protein binding95%
MetabolismLiver (mainly CYP3A4, less CYP1A2)
Elimination half-life36.2 hrs (median)
Excretion>98% as metabolites, of which >90% via feces, 9% via urine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H23N3O4
Molar mass393.443 g·mol−1
3D model (JSmol)
  (verify)

Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer.[4] Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) — either an exon 19 deletion (del19) or exon 21 (L858R) substitution mutation — which has spread to other parts of the body.[4] It is taken by mouth.[4]

Common side effects include rash, diarrhea, muscle pain, joint pain, and cough.[4][3] Serious side effects may include lung problems, kidney problems, liver failure, gastrointestinal perforation, stroke, and corneal ulceration.[4] Use in pregnancy may harm the baby.[4] It is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).[4]

Erlotinib was approved for medical use in the United States in 2004.[5][4][3] It is on the World Health Organization's List of Essential Medicines.[6]

Medical uses

Lung cancer

Erlotinib in unresectable non-small cell lung cancer when added to chemotherapy improves overall survival by 19%, and improved progression-free survival (PFS) by 29%, when compared to chemotherapy alone.[7][8][9] The U.S. Food and Drug Administration (FDA) approved erlotinib for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen.[10]

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.[11][12] 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.[12] 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.[13]

Pancreatic cancer

In November 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unresectable, or metastatic pancreatic cancer.[14]

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 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).[15]

Approximately 20% of drug resistance is caused by amplification of the hepatocyte growth factor receptor, which drives ERBB3 dependent activation of PI3K.[16][17]

Side effects

Common

  • 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. Some clinical studies have indicated a correlation between the severity of the skin reactions and increased survival though this has not been quantitatively assessed.[18] 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."[19] 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."[20]
  • Diarrhea
  • Loss of appetite
  • Fatigue[9]
  • Partial hair loss (by strands, not typically in clumps)

Rare

  • 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.
  • ingrown hairs, such as eyelashes
  • gastrointestinal tract toxicity
    • serious or fatal gastrointestinal tract perforations
  • skin toxicity
  • ocular disorders
    • corneal lesions
  • Pulmonary toxicity

Interactions

Erlotinib is not a substrate for either of hepatic OATPs (OATP1B1 or OATP1B3).[23] Also, erlotinib is not an inhibitor of OATP-1B1 or OATP-1B3 transporter.[24]

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.[25]

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.[26] 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.

Society and culture

It is marketed in the United States by Genentech[3] and OSI Pharmaceuticals[27] and elsewhere by Roche.[28]

The drug's U.S. patent will expire in 2020.[29] 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.[citation needed] In India, generic pharmaceutical firm Cipla is battling[when?] with Roche against the Indian patent for this drug.[30][31]

References

  1. ↑ "Erlotinib (Tarceva) Use During Pregnancy". 1 November 2019. https://www.drugs.com/pregnancy/erlotinib.html. 
  2. ↑ 2.0 2.1 "Tarceva® (Erlotinib hydrochloride)". Roche Products Pty Limited. Australian Product Information. 31 August 2022. https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=roptarce10415. 
  3. ↑ 3.0 3.1 3.2 3.3 "Tarceva- erlotinib hydrochloride tablet". 12 December 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57bccb29-1c47-4c64-ab6a-77960a91cc20. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Erlotinib Monograph for Professionals". https://www.drugs.com/monograph/erlotinib.html. 
  5. ↑ "Drug Approval Package: Tarceva (Erlotinib) NDA #021743". 28 March 2005. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-743_Tarceva.cfm. 
  6. ↑ Organization, World Health (2019). World Health Organization model list of essential medicines: 21st list 2019. World Health Organization. 
  7. ↑ "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.". http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=32756. 
  8. ↑ "April 2010 - Tarceva Indication Announcement Letter". http://www.tarceva.com/docs/Indication_Announcement_Letter.pdf. 
  9. ↑ 9.0 9.1 "Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer". ERJ Open Research 8 (4): 00239–2022. October 2022. doi:10.1183/23120541.00239-2022. PMID 36267895. 
  10. ↑ "FDA drug approval summary: erlotinib (Tarceva) tablets". The Oncologist 10 (7): 461–466. August 2005. doi:10.1634/theoncologist.10-7-461. PMID 16079312. 
  11. ↑ "Epidermal growth factor receptor (EGFR) mutation and personalized therapy in advanced nonsmall cell lung cancer (NSCLC)". Targeted Oncology 8 (1): 27–33. March 2013. doi:10.1007/s11523-013-0258-9. PMID 23361373. 
  12. ↑ 12.0 12.1 "Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis". Asian Pacific Journal of Cancer Prevention 13 (10): 5177–5182. 2012. doi:10.7314/APJCP.2012.13.10.5177. PMID 23244131. 
  13. ↑ "Roche obtains license for EGFR lung cancer assays and will develop Tarceva companion diagnostic test". Roche (Press release). Archived from the original on 24 February 2022. Retrieved 2020-01-10.
  14. ↑ Principles of Oncologic Pharmacotherapy, 15 April 2009, http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628, retrieved 18 June 2009 
  15. ↑ "Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors". Clinical Cancer Research 12 (21): 6494–6501. November 2006. doi:10.1158/1078-0432.CCR-06-1570. PMID 17085664. 
  16. ↑ "MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling". Science 316 (5827): 1039–1043. May 2007. doi:10.1126/science.1141478. PMID 17463250. Bibcode: 2007Sci...316.1039E. 
  17. ↑ "MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib". Proceedings of the National Academy of Sciences of the United States of America 104 (52): 20932–20937. December 2007. doi:10.1073/pnas.0710370104. PMID 18093943. Bibcode: 2007PNAS..10420932B. 
  18. ↑ "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. January 2006. doi:10.1016/j.lungcan.2005.09.002. PMID 16290256. 
  19. ↑ "Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer". Journal of Clinical Oncology 22 (16): 3238–3247. August 2004. doi:10.1200/JCO.2004.11.057. PMID 15310767. 
  20. ↑ "Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer". Journal of Clinical Oncology 1 (17): 3–4. 2003. 
  21. ↑ "Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile". Drug Metabolism and Disposition 38 (7): 1238–1245. July 2010. doi:10.1124/dmd.109.030361. PMID 20382753. 
  22. ↑ "Fatal asymmetric interstitial lung disease after erlotinib for lung cancer". Respiration; International Review of Thoracic Diseases 84 (5): 431–435. 2012. doi:10.1159/000339508. PMID 22889962. 
  23. ↑ "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions 29 (3): 179–190. March 2014. doi:10.1515/dmdi-2013-0062. PMID 24643910. 
  24. ↑ "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions 29 (4): 249–259. May 2014. doi:10.1515/dmdi-2014-0014. PMID 24807167. 
  25. ↑ Haberfeld, H, ed (2010) (in de). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag. 
  26. ↑ "Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy". Drugs 60 (Suppl 1): 15–23; discussion 41–2. 2000. doi:10.2165/00003495-200060001-00002. PMID 11129168. 
  27. ↑ Adis International Ltd (2003). "Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415". Drugs in R&D 4 (4): 243–248. doi:10.2165/00126839-200304040-00006. PMID 12848590. 
  28. ↑ "FDA Approves Roche Test as CDx for Tarceva for Treating Certain NSCLC Patients" (in en-us). 15 May 2013. https://www.genomeweb.com/diagnostics/fda-approves-roche-test-cdx-tarceva-treating-certain-nsclc-patients. 
  29. ↑ "Erlotinib - Generic Drug Details". DrugPatentWatch.com. http://drugpatentwatch.com/p/ingredient/erlotinib. 
  30. ↑ "Roche and India's Glenmark reach truce over generic Tarceva". 22 January 2016. http://www.gabionline.net/Generics/News/Roche-and-India-s-Glenmark-reach-truce-over-generic-Tarceva. 
  31. ↑ "Cancer drug: Supreme Court allows Cipla to withdraw appeal against Roche". 16 June 2017. https://economictimes.indiatimes.com/cancer-drug-supreme-court-allows-cipla-to-withdraw-appeal-against-roche/articleshow/59176743.cms. 

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