Cetuximab

In the US, cetuximab is indicated for the treatment of head and neck cancer and colorectal cancer.

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.

Cetuximab was approved by the US Food and Drug Administration (FDA) in March 2006, for use in combination with radiation therapy for treating squamous cell carcinoma of the head and neck (SCCHN) or as a single agent in people who have had prior platinum-based therapy.{{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 }} The IMCL-9815 Phase III Registration Trial, the addition of cetuximab to radiotherapy improved clinical outcomes regardless of p16 or HPV status versus radiotherapy alone.{{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 }} However, subsequent studies{{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 }} and clinical trials (NRG Oncology RTOG 1016{{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 }} and De-ESCALaTE HPV{{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 }}) suggested cetuximab was significantly inferior in overall and progression-free survival, when compared with cisplatin.

In July 2009, the U.S. Food and Drug Administration (FDA) approved cetuximab for the treatment of colon cancer with wild-type KRAS.{{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 }}{{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}}

One of the more serious side effects of cetuximab therapy is the incidence of acne-like rash. It is generally reversible.{{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 }}

Further severe infusion reactions include but are not limited to: fevers, chills, rigors, urticaria, itchiness, rash, hypotension, nausea, vomiting, headache, shortness of breath, wheezing, angioedema, dizziness, anaphylaxis, and cardiac arrest. Other common side effects include photosensitivity, hypomagnesemia due to magnesium wasting, and less commonly pulmonary and cardiac toxicity.8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically

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.{{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 }}

Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR.{{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 }}

The KRAS 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.{{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 }}{{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 }}

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.{{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. Food and Drug Administration (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 }}

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.{{medcn|date=February 2016}} Around 65% of mCRC patients have the KRAS wild-type gene.{{medcn|date=February 2016}}

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).{{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 }} 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.{{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 }}{{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 }}

Observations on EGFR inhibition were published in 1988.{{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 }} Yeda Research, on behalf of the Weizmann Institute of Science in Israel,{{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 }} challenged the Aventis-owned patent,{{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 }} licensed by Imclone, for the use of anti-epidermal growth factor receptor antibodies in combination with chemotherapy, to slow the growth of certain tumors which was filed in 1989 by Rhone-Poulenc-Rorer.{{ 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 }} 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.{{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 }}{{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 }}{{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 }}

• Eli Lilly and Company 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.
• Merck KGaA manufactures Erbitux for supply in its territory (outside the U.S. and Canada) as well as for Japan.{{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 }}

• 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.

Cetuximab is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.{{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 }}

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.{{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 }}

Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion.{{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 }}

{{see also|Biosimilars}}

{{Asof|2023}}, there are no biosimilars of cetuximab.{{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 }}

{{Main|ImClone stock trading case}}

Cetuximab failed to get FDA approval in 2001, which caused the stock price of the developer ImClone to drop dramatically. Prior to the announcement, several executives sold stock, and the SEC launched an investigation into insider trading. This resulted in a widely publicized criminal case, which resulted in prison terms for media celebrity Martha Stewart, ImClone chief executive officer Samuel D. Waksal and Stewart's broker at Merrill Lynch, Peter Bacanovic.{{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 }}{{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 }}

The efficacy of cetuximab was explored in a clinical trial of advanced gastric cancer published in 2013; cetuximab showed no survival benefit.{{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 }}

A 2020 phase III multicenter randomized controlled trial headed by University College London 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.{{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 }}

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.{{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 }}

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