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Revision as of 21:06, 10 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,071 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL').← Previous edit Latest revision as of 02:40, 26 September 2024 edit undoHeyElliott (talk | contribs)Extended confirmed users119,346 edits MOS:NUMERALTag: 2017 wikitext editor 
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{{Short description|Pharmaceutical drug}}
{{Drugbox
{{Use dmy dates|date=August 2024}}
| image =
{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug
<!--Monoclonal antibody data-->
| Verifiedfields = changed
| verifiedrevid = 460026782
| type = mab | type = mab
| image = Cetuximab.png
| width =
| alt =
| caption =

<!-- Monoclonal antibody data -->
| mab_type = mab | mab_type = mab
| source = xi/o | source = xi/o
| target = ] | target = ]


<!--Clinical data--> <!-- Clinical data -->
| tradename = | pronounce =
| tradename = Erbitux
| Drugs.com = {{drugs.com|monograph|cetuximab}} | Drugs.com = {{drugs.com|monograph|cetuximab}}
| MedlinePlus =
| routes_of_administration = ]
| DailyMedID = Cetuximab
| pregnancy_AU = D
| pregnancy_AU_comment =
| pregnancy_category =
| routes_of_administration = ]
| class =
| ATC_prefix = L01
| ATC_suffix = FE01
| ATC_supplemental =
| biosimilars =


<!--Pharmacokinetic data--> <!-- Legal status -->
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| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Erbitux FDA label">{{cite web | title=Erbitux- cetuximab solution | website=DailyMed | date=27 September 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bc6397e-4bd8-4d37-a007-a327e4da34d9 | access-date=2 June 2022 | archive-date=20 October 2021 | archive-url=https://web.archive.org/web/20211020211052/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bc6397e-4bd8-4d37-a007-a327e4da34d9 | url-status=live }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Erbitux EPAR">{{cite web | title=Erbitux EPAR | website=] | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/erbitux | access-date=2 June 2022 | archive-date=14 May 2021 | archive-url=https://web.archive.org/web/20210514113705/https://www.ema.europa.eu/en/medicines/human/EPAR/erbitux | url-status=live }}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life = 114 hrs | elimination_half-life = 114 hrs
| duration_of_action =
| excretion =


<!--Identifiers--> <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| ChemSpiderID = NA
| CAS_number = 205923-56-4 | CAS_number = 205923-56-4
| CAS_supplemental =
| ATC_prefix = L01
| PubChem =
| ATC_suffix = XC06
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00002 | DrugBank = DB00002
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
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| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
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| KEGG_Ref = {{keggcite|correct|kegg}}
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| ChEMBL_Ref = {{ebicite|changed|EBI}}
| C=6484 | H=10042 | N=1732 | O=2023 | S=36
| ChEMBL = 1201577
| molecular_weight = 145781.6 g/mol
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =

<!-- Chemical and physical data -->
| C=6484 | H=10042 | N=1732 | O=2023 | S=36
}} }}


'''Cetuximab''' (IMC-C225—marketed under the name '''Erbitux''') is a chimeric (mouse/human) monoclonal antibody, an epidermal growth factor receptor (EGFR) inhibitor, given by intravenous infusion for treatment of metastatic ] and ]. '''Cetuximab''', sold under the brand name '''Erbitux''', is an ] (EGFR) inhibitor ] used for the treatment of metastatic ] and ].<ref name="Erbitux FDA label" /> Cetuximab is a chimeric (mouse/human) ] given by ].<ref name="Erbitux FDA label" />


Cetuximab was approved for medical use in the United States in 2004.<ref>{{cite web | title=Drug Approval Package: Erbitux BLA 125084 | website=accessdata.fda.gov | date=13 September 2004 | url=https://www.accessdata.fda.gov/drugsatfda_docs/bla/2004/125084_erbitux_toc.cfm | access-date=17 August 2024}}</ref>
== Distribution ==


== Medical uses ==
Cetuximab is manufactured and distributed in North America by ] and Bristol-Myers Squibb, while in the rest of the world distribution is by Merck KGaA. Cetuximab is given by ] and costs up to $30,000 for eight weeks of treatment per patient.<ref name="Schrag">{{cite journal | last =Schrag | first =D | authorlink = | coauthors = | title =The price tag on progress &ndash; chemotherapy for colorectal cancer | journal =New England Journal of Medicine | volume =351 | issue =4 | pages =317–319 | publisher = | month =July | year =2004 | url =http://content.nejm.org/cgi/content/extract/351/4/317 | doi = 10.1056/NEJMp048143| id = | accessdate =| pmid =15269308 }}</ref>
In the US, cetuximab is ] for the treatment of head and neck cancer and colorectal cancer.<ref name="Erbitux FDA label" />


In the EU, cetuximab is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer and for the treatment of squamous cell cancer of the head and neck.<ref name="Erbitux EPAR" />
== Indications ==


=== Head and neck cancer ===
Cetuximab is indicated for the treatment of patients with ] (EGFR)-expressing, ] wild-type metastatic ] (mCRC), in combination with chemotherapy, and as a single agent in patients who have failed ]- and ]-based therapy and who are intolerant to irinotecan. The positive opinion from the Committee for Medicinal Products for Human Use (CHMP) was received for mCRC 1st line use in May 2008.{{citation needed|date=December 2010}}
Cetuximab was approved by the US ] (FDA) in March 2006, for use in combination with ] for treating ] of the head and neck (]) or as a single agent in people who have had prior platinum-based therapy.<ref>{{cite web |url=http://www.cancer.gov/clinicaltrials/results/head-neck-cetuximab0604 |title=Cetuximab Beneficial in Head and Neck Cancer |publisher=Cancer.gov National Cancer Institute |access-date=2013-04-13 |archive-url=https://web.archive.org/web/20101221093149/http://www.cancer.gov/clinicaltrials/results/head-neck-cetuximab0604 |archive-date=2010-12-21 }}</ref> The IMCL-9815 Phase III Registration Trial, the addition of cetuximab to radiotherapy improved clinical outcomes regardless of ] or ] versus radiotherapy alone.<ref>{{cite journal | vauthors = Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA | title = Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab | journal = Journal of Clinical Oncology | volume = 34 | issue = 12 | pages = 1300–1308 | date = April 2016 | pmid = 26712222 | pmc = 5070577 | doi = 10.1200/JCO.2015.62.5970 }}</ref> However, subsequent studies<ref>{{cite journal | vauthors = Jeong IS, Mo H, Nguyen A, Chong EG, Tsai HH, Moyers J, Kim M, Lacy C, Shah V, Lau E, Xu Y, Cao H | title = Primary chemoradiation with cisplatin versus cetuximab for locally advanced head and neck cancer: a retrospective cohort study | journal = Experimental Hematology & Oncology | volume = 9 | pages = 19 | date = 2020 | pmid = 32775042 | pmc = 7409407 | doi = 10.1186/s40164-020-00175-1 | doi-access = free }}</ref> and clinical trials (NRG Oncology RTOG 1016<ref>{{cite journal | vauthors = Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Jordan RC, Zhao W, Sturgis EM, Burtness B, Ridge JA, Ringash J, Galvin J, Yao M, Koyfman SA, Blakaj DM, Razaq MA, Colevas AD, Beitler JJ, Jones CU, Dunlap NE, Seaward SA, Spencer S, Galloway TJ, Phan J, Dignam JJ, Le QT | title = Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial | journal = Lancet | volume = 393 | issue = 10166 | pages = 40–50 | date = January 2019 | pmid = 30449625 | pmc = 6541928 | doi = 10.1016/S0140-6736(18)32779-X }}</ref> and De-ESCALaTE HPV<ref>{{cite journal | vauthors = Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, Dalby M, Mistry P, Sen M, O'Toole L, Al Booz H, Dyker K, Moleron R, Whitaker S, Brennan S, Cook A, Griffin M, Aynsley E, Rolles M, De Winton E, Chan A, Srinivasan D, Nixon I, Grumett J, Leemans CR, Buter J, Henderson J, Harrington K, McConkey C, Gray A, Dunn J | title = Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial | journal = Lancet | volume = 393 | issue = 10166 | pages = 51–60 | date = January 2019 | pmid = 30449623 | pmc = 6319250 | doi = 10.1016/S0140-6736(18)32752-1 }}</ref>) suggested cetuximab was significantly inferior in overall and progression-free survival, when compared with ].
Cetuximab (Erbitux) is indicated for the treatment of patients with ] in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease. The positive CHMP opinion for this indication was received in October 2008.{{citation needed|date=December 2010}}


=== Colorectal cancer ===
A diagnostic immunohistochemistry assay (EGFR pharmDx) can be used to detect EGFR expression in the tumor material. Approximately 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor and are therefore considered eligible for treatment with cetuximab or ].{{citation needed|date=December 2010}}
In July 2009, the U.S. ] (FDA) approved cetuximab for the treatment of colon cancer with wild-type ].<ref>{{Cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/125084s0167ltr.pdf |title=Archived copy |access-date=17 August 2024 |archive-date=17 August 2024 |archive-url=https://web.archive.org/web/20240817060527/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/125084s0167ltr.pdf |url-status=live }}</ref><ref>{{cite web | title=Erbitux (cetuximab) Solution for intravenous infusion | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=12227 | access-date=17 August 2024}}</ref>


== Biomarkers == == Side effects ==
One of the more serious side effects of cetuximab therapy is the incidence of ]. It is generally reversible.<ref name="pmid19925924">{{cite journal | vauthors = Nguyen A, Hoang V, Laquer V, Kelly KM | title = Angiogenesis in cutaneous disease: part I | journal = Journal of the American Academy of Dermatology | volume = 61 | issue = 6 | pages = 921–42; quiz 943–4 | date = December 2009 | pmid = 19925924 | doi = 10.1016/j.jaad.2009.05.052 | s2cid = 2618247 | url = https://www.escholarship.org/uc/item/5p17d7d9 | access-date = 17 May 2023 | archive-date = 17 August 2024 | archive-url = https://web.archive.org/web/20240817052851/https://escholarship.org/uc/item/5p17d7d9 | url-status = live }}</ref>


Further severe infusion reactions include but are not limited to: fevers, chills, ], ], ], rash, hypotension, nausea, vomiting, headache, shortness of breath, wheezing, angioedema, dizziness, ], and cardiac arrest. Other common side effects include photosensitivity, ] due to magnesium wasting, and less commonly pulmonary and cardiac toxicity.<ref>8. Micromedex Healthcare Series . Greenwood Village, Colo: Thomson Healthcare. Updated periodically</ref>
In mCRC, ]s, including KRAS, are indicative of response to cetuximab (Erbitux). 60% of patients express the KRAS wild-type tumor and data have shown that these patients are significantly more likely to benefit from treatment with cetuximab or a combination of cetuximab plus chemotherapy. Two recent studies demonstrated that patients with KRAS wild-type tumors demonstrated significantly increased response rates and disease free survival when treated with cetuximab and standard chemotherapy (OPUS AND CRYSTAL), compared to patients receiving chemotherapy alone.


=== Alpha-gal allergy ===
There is increasing evidence to support the use of biomarkers in predicting tumor response to treatment, as this allows therapeutic approaches to be tailored or personalized to individual patients and results in improved outcomes and survival. While there remains some scientific controversy on this, assessment for EGFR expression is required for the use of cetuximab (Erbitux) in Colorectal Cancer, but not in Head & Neck Cancer.
Certain geographic regions have a high rate of anaphylactic reactions to cetuximab upon the first exposure to the medication. This is unusual because exposure to the allergen must occur before the development of an allergy. Fewer than 1% of people in the northeast United States reacted, while greater than 20% in the southeast did.<ref>{{cite journal | vauthors = Berg EA, Platts-Mills TA, Commins SP | title = Drug allergens and food--the cetuximab and galactose-α-1,3-galactose story | journal = Annals of Allergy, Asthma & Immunology | volume = 112 | issue = 2 | pages = 97–101 | date = February 2014 | pmid = 24468247 | pmc = 3964477 | doi = 10.1016/j.anai.2013.11.014 }}</ref><ref name=Chi2008/>


== Clinical uses == == Mechanism of action ==
Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR.<ref name=Chi2008>{{cite journal | vauthors = Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA | title = Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose | journal = The New England Journal of Medicine | volume = 358 | issue = 11 | pages = 1109–1117 | date = March 2008 | pmid = 18337601 | pmc = 2361129 | doi = 10.1056/NEJMoa074943 }}</ref>
=== Colorectal cancer ===


== KRAS Testing ==
Cetuximab is indicated for the treatment of patients with EGFR expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy or as a single agent in patients who have failed in oxaliplatin- or irinotecan- base therapy and who are intolerant to irinotecan. While there remains some scientific controversy on this, assessment for EGFR expression is required for use in colorectal cancer, but not in head & neck cancer.
The ] gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors in which KRAS is not mutated.<ref name="pmid19339720">{{cite journal | vauthors = Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P | title = Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer | journal = The New England Journal of Medicine | volume = 360 | issue = 14 | pages = 1408–1417 | date = April 2009 | pmid = 19339720 | doi = 10.1056/NEJMoa0805019 | doi-access = free }}</ref><ref name="pmid22446022">{{cite journal | vauthors = Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH | title = Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials | journal = European Journal of Cancer | volume = 48 | issue = 10 | pages = 1466–1475 | date = July 2012 | pmid = 22446022 | doi = 10.1016/j.ejca.2012.02.057 | doi-access = free }}</ref>


In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (] (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.<ref>{{cite web | url = https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm172905.htm | title = Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations | date = 2010-01-11 | publisher = U.S. ] (FDA) | access-date = 2019-12-16 | archive-date = 2016-10-24 | archive-url = https://web.archive.org/web/20161024005434/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm172905.htm | url-status = dead }}</ref>
Many clinical trials have been conducted to investigate the efficacy of cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and there is increasing evidence to support the use of biomarkers, such as KRAS, to predict tumor response to anti-EGFR therapies. Two large clinical trials of cetuximab, OPUS<ref name="pmid19114683">{{cite journal | author = Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P | title = Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer | journal = J. Clin. Oncol. | volume = 27 | issue = 5 | pages = 663–71 | year = 2009 | month = February | pmid = 19114683 | doi = 10.1200/JCO.2008.20.8397 | url = }}</ref> and CRYSTAL,<ref name="pmid19339720">{{cite journal | author = Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P | title = Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer | journal = N. Engl. J. Med. | volume = 360 | issue = 14 | pages = 1408–17 | year = 2009 | month = April | pmid = 19339720 | doi = 10.1056/NEJMoa0805019 | url = }}</ref> have recently been published, and have provided further evidence that cetuximab significantly improves response rates and disease free survival rates in mCRC patients with KRAS wild-type tumors.


Studies have indicated that detection of KRAS gene mutations helps physicians identify patients that are unlikely to respond to treatment with targeted EGFR inhibitors, including cetuximab and panitumumab. Accordingly, ] to confirm the absence of KRAS mutations (and so the presence of the KRAS wild-type gene), is now clinically routine before the start of treatment with EGFR inhibitors. mCRC patients with wild-type KRAS tumors have been shown to benefit from a response rate of over 60% and a decreased risk for progression of over 40% when treated with Erbitux as 1st-line therapy.{{medcn|date=February 2016}} Around 65% of mCRC patients have the KRAS wild-type gene.{{medcn|date=February 2016}}
A study in June 2010 found that Erbitux failed to benefit patients with less advanced (non-metastasized) stages of colorectal cancer with no improvement in survival rates. Adding Erbitux instead increased the side effects of chemotherapy.
Several recent studies showed:


There is some evidence that colorectal tumors with the ''KRAS'' G13D mutation (glycine to aspartate at codon 13) respond to EGFR inhibition (specifically, with Cetuximab).<ref name="De_Roock2010-rx">{{cite journal | vauthors = De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O'Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, Tejpar S | title = Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab | journal = JAMA | volume = 304 | issue = 16 | pages = 1812–1820 | date = October 2010 | pmid = 20978259 | doi = 10.1001/jama.2010.1535 | doi-access = free }}</ref> While the mechanism is still under investigation, current findings suggest that susceptibility to EGFR-inhibition is due to how this particular variant maintains interactions with the GTPase activating protein (GAP) ''NFI''.<ref name="McFall2019-og">{{cite journal | vauthors = McFall T, Diedrich JK, Mengistu M, Littlechild SL, Paskvan KV, Sisk-Hackworth L, Moresco JJ, Shaw AS, Stites EC | title = A systems mechanism for KRAS mutant allele-specific responses to targeted therapy | journal = Science Signaling | volume = 12 | issue = 600 | pages = 8288 | date = September 2019 | pmid = 31551296 | pmc = 6864030 | doi = 10.1126/scisignal.aaw8288 }}</ref><ref name="Rabara2019-wk">{{cite journal | vauthors = Rabara D, Tran TH, Dharmaiah S, Stephens RM, McCormick F, Simanshu DK, Holderfield M | title = KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 44 | pages = 22122–22131 | date = October 2019 | pmid = 31611389 | pmc = 6825300 | doi = 10.1073/pnas.1908353116 | doi-access = free | bibcode = 2019PNAS..11622122R }}</ref>
Adding the targeted drug cetuximab to a three-drug chemotherapy regimen for first-line treatment of metastatic colorectal cancer does not improve response rate, progression-free survival or overall survival, researchers reported at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy


==History==
A second Phase III study (COIN) of cetuximab in combination with capecitabine and oxaliplatin versus chemotherapy alone in first-line mCRC, did not meet its primary endpoint of overall survival in K-ras wild type patients (17 months vs. 17.9 months; HR 1.038; 95% CI 0.90 - 1.20; p=0.68).
Observations on EGFR inhibition were published in 1988.<ref>{{cite journal | vauthors = Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M | title = Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice | journal = Journal of the National Cancer Institute | volume = 80 | issue = 20 | pages = 1605–1611 | date = December 1988 | pmid = 3193478 | doi = 10.1093/jnci/80.20.1605 }}</ref> Yeda Research, on behalf of the ] in Israel,<ref name="urlwww.yedarnd.com">{{cite web | url = http://www.yedarnd.com/+ | title = Yeda Research and Development Company Ltd | quote = Technology Transfer Company of the Weizmann Institute of Science | access-date = 2013-01-05 | archive-url = https://web.archive.org/web/20161204093338/http://www.yedarnd.com/ | archive-date = 2016-12-04 }}</ref> challenged the Aventis-owned patent,<ref name="Groombridge_Gearing">{{cite journal | vauthors = Groombridge N, Gearing BP | title = Practical lessons from a "made for TV" patent litigation: The trial of Yeda Research & Development Co. Ltd. v. ImClone Systems Inc. and Aventis Pharmaceuticals Inc. | journal = The Federal Lawyer | pages = 51–55 | date = February 2008 | url = http://www.yedarnd.com/images/pics/UserImages/Practical_Lessons%20from%20a%20Made%20for%20TV%20Patent%20Litigation.pdf | archive-url = https://web.archive.org/web/20090903012733/http://www.yedarnd.com/images/pics/UserImages/Practical_Lessons%20from%20a%20Made%20for%20TV%20Patent%20Litigation.pdf | archive-date = 2009-09-03 }}</ref> licensed by ], for the use of anti-] antibodies in combination with chemotherapy, to slow the growth of certain tumors which was filed in 1989 by ].<ref name = "US6217866">{{ cite patent | country = US | number = 6217866 | status = patent | title = Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same | pubdate = 2001-04-17 | fdate = 1995-06-07 | inventor = Sela M, Pirak E, Hurwitz E | assign1 = Yeda Research & Development }}</ref> The court ruled that Yeda is sole owner of the patent in the U.S., while Yeda and Sanofi-Aventis co-own the patent's foreign counterparts.<ref>{{cite web |url=http://www.nysd.uscourts.gov/rulings/03CV08484_opinion_091806.pdf |title=Court ruling on Yeda vs Aventis/Imclone case |access-date=2012-05-25 |archive-url=https://web.archive.org/web/20110927101421/http://www.nysd.uscourts.gov/rulings/03CV08484_opinion_091806.pdf |archive-date=2011-09-27 }}</ref><ref>{{cite web|url=http://www.legalmetric.com/cases/patent/nysd/nysd_103cv08484.html |title=Yeda Research v. Imclone Systems, et al |access-date=2015-08-30 |archive-url=https://web.archive.org/web/20151120002423/http://www.legalmetric.com/cases/patent/nysd/nysd_103cv08484.html |archive-date=2015-11-20 }}</ref><ref name=USA>{{cite news | url = https://www.usatoday.com/money/industries/health/drugs/2006-09-14-imclone-usat_x.htm | title = ImClone goes up against patent dispute | date = 2006-09-14 | work = USA Today | access-date = 2017-08-25 | archive-date = 2008-02-02 | archive-url = https://web.archive.org/web/20080202053326/http://www.usatoday.com/money/industries/health/drugs/2006-09-14-imclone-usat_x.htm | url-status = live }}</ref>


=== Head and neck cancer === ==Society and culture==
Cetuximab was approved by the ] in March 2006<ref></ref> for use in combination with ] for treating ] of the head and neck (]) or as a single agent in patients who have had prior platinum-based therapy.


===Manufacture===
Two landmark studies have evaluated the benefits of cetuximab (Erbitux) in patients with SCCHN in both the locally advanced (Bonner trial) and the recurrent and/or metastatic (EXTREME trial) settings. The EXTREME trial is the first time in 30 years that a Phase III trial has demonstrated a survival benefit in 1st-line recurrent and/or metastatic disease. Erbitux was granted approval by the European Commission in November 2008 for the treatment of 1st-line recurrent and/or metastatic SCCHN based on the results of the EXTREME study.{{citation needed|date=December 2010}}
* ] is responsible for the manufacture and supply of Erbitux in bulk-form active pharmaceutical ingredient (API) for clinical and commercial use in the U.S. and Canada.
* ] manufactures Erbitux for supply in its territory (outside the U.S. and Canada) as well as for Japan.<ref name="investor.lilly.com">{{Cite web |url=https://investor.lilly.com/financials.cfm |title=Eli Lilly and Company Form 10-K Annual Report 2013 |access-date=2014-09-22 |archive-date=2017-05-04 |archive-url=https://web.archive.org/web/20170504013929/https://investor.lilly.com/financials.cfm |url-status=live }}</ref>


== Resistance == ===Distribution===
* Erbitux is marketed in the U.S. and Canada by Eli Lilly.
* Outside the U.S. and Canada, Erbitux is commercialized by Merck KGaA. Eli Lilly receives royalties from Merck KGaA.
* A separate agreement grants co-exclusive rights among Merck, Bristol-Myers Squibb and Eli Lilly in Japan and expires in 2032.<ref name="investor.lilly.com"/>


===Economics===
In September 2011, researchers at the ] showed that resistance to cetuximab was likely to be mediated via signalling through the ] protein - either through upregulation of protein production or overexpression of the gene. <ref name="YonesakaZejnullahu2011">{{cite journal|last1=Yonesaka|first1=K.|last2=Zejnullahu|first2=K.|last3=Okamoto|first3=I.|last4=Satoh|first4=T.|last5=Cappuzzo|first5=F.|last6=Souglakos|first6=J.|last7=Ercan|first7=D.|last8=Rogers|first8=A.|last9=Roncalli|first9=M.|last10=Takeda|first10=M.|last11=Fujisaka|first11=Y.|last12=Philips|first12=J.|last13=Shimizu|first13=T.|last14=Maenishi|first14=O.|last15=Cho|first15=Y.|last16=Sun|first16=J.|last17=Destro|first17=A.|last18=Taira|first18=K.|last19=Takeda|first19=K.|last20=Okabe|first20=T.|last21=Swanson|first21=J.|last22=Itoh|first22=H.|last23=Takada|first23=M.|last24=Lifshits|first24=E.|last25=Okuno|first25=K.|last26=Engelman|first26=J. A.|last27=Shivdasani|first27=R. A.|last28=Nishio|first28=K.|last29=Fukuoka|first29=M.|last30=Varella-Garcia|first30=M.|last31=Nakagawa|first31=K.|last32=Janne|first32=P. A.|title=Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab|journal=Science Translational Medicine|volume=3|issue=99|year=2011|pages=99ra86–99ra86|issn=1946-6234|doi=10.1126/scitranslmed.3002442}}</ref> This opens up the possibility that combination therapy with HER2/neu-targeting drugs such as ] or ] may prove effective, although as yet this is unproven.


Cetuximab is given by ] and costs up to $30,000 for eight weeks of treatment per patient.<ref name="Schrag">{{cite journal | vauthors = Schrag D | title = The price tag on progress--chemotherapy for colorectal cancer | journal = The New England Journal of Medicine | volume = 351 | issue = 4 | pages = 317–319 | date = July 2004 | pmid = 15269308 | doi = 10.1056/NEJMp048143 }}</ref>
== Side effects ==
One of the more serious side effects of Cetuximab therapy is the incidence of ]. This rash rarely leads to dose reductions or termination of therapy. It is generally reversible.<ref name="pmid19925924">{{cite journal |author=Nguyen A, Hoang V, Laquer V, Kelly KM |title=Angiogenesis in cutaneous disease: part I |journal=J. Am. Acad. Dermatol. |volume=61 |issue=6 |pages=921–42; quiz 943–4 |year=2009 |month=December |pmid=19925924 |doi=10.1016/j.jaad.2009.05.052 |url=}}</ref>


Merck KGaA had 887 million euros ($1.15 billion) in Erbitux sales in 2012, from head and neck as well as bowel cancer, while Bristol-Myers Squibb generated $702 million in sales from the drug.<ref>{{Cite web |url=http://in.reuters.com/article/us-erbitux-avastin-idINBRE95006O20130601?goback=.gde_1008637_member_245962179 |title=Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013 |access-date=2021-07-06 |archive-date=2016-03-06 |archive-url=https://web.archive.org/web/20160306161818/http://in.reuters.com/article/us-erbitux-avastin-idINBRE95006O20130601?goback=.gde_1008637_member_245962179 |url-status=dead }}</ref>
As well as severe infusion reactions including but not limited to: fevers, chills, ], ], ], rash, hypotension, N/V, HA, bronchospasm, dyspnea, wheezing, angioedema, dizziness, ], and cardiac arrest. Therefore, pretreatment with ] 30-60 min. before administration is standard of care. Other common side effects include photosensitivity, ] due to magnesium wasting, and less commonly pulmonary and cardiac toxicity.
<ref>8. Micromedex Healthcare Series . Greenwood Village, Colo: Thomson Healthcare. Updated periodically
</ref>


Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion.<ref>{{Cite web |url=http://www.fiercepharma.com/special-reports/top-10-best-selling-cancer-drugs-2013 |title=Top 10 best-selling cancer drugs of 2013; May 29, 2014 |access-date=September 20, 2014 |archive-date=April 13, 2016 |archive-url=https://web.archive.org/web/20160413234945/http://www.fiercepharma.com/special-reports/top-10-best-selling-cancer-drugs-2013 |url-status=live }}</ref>
== KRAS Testing ==

===Biosimilars===
{{see also|Biosimilars}}

{{Asof|2023}}, there are no biosimilars of cetuximab.<ref>{{cite journal | vauthors = Douez E, D'Atri V, Guillarme D, Antier D, Guerriaud M, Beck A, Watier H, Foucault-Fruchard L | title = Why is there no biosimilar of Erbitux? | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 234 | issue = | pages = 115544 | date = September 2023 | pmid = 37418870 | doi = 10.1016/j.jpba.2023.115544 | doi-access = free | title-link = doi }}</ref>


=== Insider trading ===
The ] gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors that are not mutated.<ref>http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34491</ref><ref>Cetuximab and chemotherapy as initial treatment for metastatic colorecal cancer, Eric Van Cutsem, et all, N Engl J Med 360:1408</ref>
{{Main|ImClone stock trading case}}
Cetuximab failed to get FDA approval in 2001, which caused the stock price of the developer ] to drop dramatically. Prior to the announcement, several executives sold stock, and the SEC launched an investigation into ]. This resulted in a widely publicized criminal case, which resulted in prison terms for media celebrity ], ImClone chief executive officer ] and Stewart's broker at ], Peter Bacanovic.<ref>{{cite news | title=MARTHA STEWART'S SENTENCE: THE OVERVIEW; 5 Months in Jail, and Stewart Vows, 'I'll Be Back' | website=The New York Times | date=17 July 2004 | url=https://www.nytimes.com/2004/07/17/business/martha-stewart-s-sentence-overview-5-months-jail-stewart-vows-ll-be-back.html | access-date=2 June 2022 | archive-date=17 August 2024 | archive-url=https://web.archive.org/web/20240817052806/https://www.nytimes.com/2004/07/17/business/martha-stewart-s-sentence-overview-5-months-jail-stewart-vows-ll-be-back.html | url-status=live }}</ref><ref>{{cite news | vauthors=Bennett C | title='HALF' LIFE OF MARTHA CONVICT | website=New York Post | date=19 August 2008 | url=https://nypost.com/2008/08/19/half-life-of-martha-convict/ | access-date=2 June 2022 | archive-date=17 August 2024 | archive-url=https://web.archive.org/web/20240817052809/https://nypost.com/2008/08/19/half-life-of-martha-convict/ | url-status=live }}</ref>


==Research==
KRAS mutational analysis is commercially available from a number of laboratories.
The efficacy of cetuximab was explored in a clinical trial of advanced ] published in 2013; cetuximab showed no survival benefit.<ref>{{cite journal | vauthors = Li K, Li J | title = Current Molecular Targeted Therapy in Advanced Gastric Cancer: A Comprehensive Review of Therapeutic Mechanism, Clinical Trials, and Practical Application | journal = Gastroenterology Research and Practice | volume = 2016 | pages = 4105615 | year = 2016 | pmid = 26880889 | pmc = 4736909 | doi = 10.1155/2016/4105615 | doi-access = free }}</ref>


A 2020 phase III multicenter randomized controlled trial headed by ] showed that adding cetuximab to perioperative chemotherapy worsened survival for colorectal cancer patients with operable liver metastases. With over five years of follow-up, median overall survival (OS) dropped from 81 months for patients treated with chemotherapy alone before and after liver resection, to 55.4 months for those that also received cetuximab.<ref name="Bridgewater_2020">{{cite journal | vauthors = Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, Stanton L, Radford M, Corkhill A, Griffiths GO, Falk S, Valle JW, O'Reilly D, Siriwardena AK, Hornbuckle J, Rees M, Iveson TJ, Hickish T, Garden OJ, Cunningham D, Maughan TS, Primrose JN | title = Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial | journal = The Lancet. Oncology | volume = 21 | issue = 3 | pages = 398–411 | date = March 2020 | pmid = 32014119 | pmc = 7052737 | doi = 10.1016/S1470-2045(19)30798-3 }}</ref>
In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (] (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.<ref>{{cite web| url=http://www.oncogenetics.org/web/fda-updates-vectibix-and-erbitux-labels-with-kras-testing-info | title=FDA updates Vectibix and Erbitux labels with KRAS testing info| author=OncoGenetics.Org| publisher=OncoGenetics.Org| accessdate=2009-07-20| month=July | year=2009}} {{Dead link|date=October 2010|bot=H3llBot}}</ref>


A multicenter, single arm, phase II study is being conducted that is designed to evaluate the efficacy and safety of cetuximab for the treatment of advanced (unresectable)/metastatic, chordoma.<ref name="ClinicalTrials.gov Identifier: NCT05041127">{{cite web |title=Cetuximab for the Treatment of Advanced Unresectable or Metastatic Chordoma |date=June 2022 |url=https://clinicaltrials.gov/ct2/show/NCT05041127 |publisher=U.S. National Institutes of Health |access-date=4 September 2022 |archive-date=17 August 2024 |archive-url=https://web.archive.org/web/20240817052823/https://clinicaltrials.gov/study/NCT05041127 |url-status=live }}</ref>
Studies have indicated that detection of KRAS gene mutations helps physicians identify patients that are unlikely to respond to treatment with targeted EGFR inhibitors, including cetuximab and panitumumab. Accordingly, genetic testing to confirm the absence of KRAS mutations (and so the presence of the KRAS wild-type gene), is now clinically routine before the start of treatment with EGFR inhibitors. mCRC patients with wild-type KRAS tumors have been shown to benefit from a response rate of over 60% and a decreased risk for progression of over 40% when treated with Erbitux as 1st-line therapy.<ref name="pmid19114683"/> Recent data suggest that around 65% of mCRC patients have the KRAS wild-type gene.<ref name="pmid19339720"/>


== References == == References ==
{{reflist|2}} {{Reflist}}


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