Cetuximab Explained

Verifiedfields:changed
Verifiedrevid:460026782
Type:mab
Mab Type:mab
Source:xi/o
Target:EGF receptor
Tradename:Erbitux
Dailymedid:Cetuximab
Pregnancy Au:D
Routes Of Administration:Intravenous
Atc Prefix:L01
Atc Suffix:FE01
Legal Au:S4
Legal Ca:Rx-only
Legal Uk:POM
Legal Us:Rx-only
Legal Us Comment:[1]
Legal Eu:Rx-only
Legal Eu Comment:[2]
Elimination Half-Life:114 hrs
Cas Number:205923-56-4
Drugbank:DB00002
Chemspiderid:none
Unii:PQX0D8J21J
Kegg:D03455
Chembl:1201577
C:6484
H:10042
N:1732
O:2023
S:36

Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion.

Cetuximab was approved for medical use in the United States in 2004.[3]

Medical uses

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.

Head and neck cancer

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.[4] 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.[5] However, subsequent studies[6] and clinical trials (NRG Oncology RTOG 1016[7] and De-ESCALaTE HPV[8]) suggested cetuximab was significantly inferior in overall and progression-free survival, when compared with cisplatin.

Colorectal cancer

In July 2009, the U.S. Food and Drug Administration (FDA) approved cetuximab for the treatment of colon cancer with wild-type KRAS.[9] [10]

Side effects

One of the more serious side effects of cetuximab therapy is the incidence of acne-like rash. It is generally reversible.[11]

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.[12]

Alpha-gal allergy

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.[13]

Mechanism of action

Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR.[14]

KRAS Testing

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.[15] [16]

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.[17]

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. Around 65% of mCRC patients have the KRAS wild-type gene.

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).[18] 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.[19] [20]

History

Observations on EGFR inhibition were published in 1988.[21] Yeda Research, on behalf of the Weizmann Institute of Science in Israel,[22] challenged the Aventis-owned patent,[23] 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.[24] 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.[25] [26] [27]

Society and culture

Manufacture

Distribution

Economics

Cetuximab is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.[29]

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.[30]

Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion.[31]

Biosimilars

See also: Biosimilars.

, there are no biosimilars of cetuximab.[32]

Insider trading

See main article: 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.[33] [34]

Research

The efficacy of cetuximab was explored in a clinical trial of advanced gastric cancer published in 2013; cetuximab showed no survival benefit.[35]

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 5 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.[36]

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.[37]

Notes and References

  1. Web site: Erbitux- cetuximab solution . DailyMed . 27 September 2021 . 2 June 2022 . 20 October 2021 . https://web.archive.org/web/20211020211052/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bc6397e-4bd8-4d37-a007-a327e4da34d9 . live .
  2. Web site: Erbitux EPAR . . 17 September 2018 . 2 June 2022 . 14 May 2021 . https://web.archive.org/web/20210514113705/https://www.ema.europa.eu/en/medicines/human/EPAR/erbitux . live .
  3. Web site: Drug Approval Package: Erbitux BLA 125084 . accessdata.fda.gov . 13 September 2004 . 17 August 2024.
  4. Web site: Cetuximab Beneficial in Head and Neck Cancer . Cancer.gov National Cancer Institute . 2013-04-13 . https://web.archive.org/web/20101221093149/http://www.cancer.gov/clinicaltrials/results/head-neck-cetuximab0604 . 2010-12-21 .
  5. Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA . 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 of Clinical Oncology . 34 . 12 . 1300–1308 . April 2016 . 26712222 . 5070577 . 10.1200/JCO.2015.62.5970 .
  6. Jeong IS, Mo H, Nguyen A, Chong EG, Tsai HH, Moyers J, Kim M, Lacy C, Shah V, Lau E, Xu Y, Cao H . Primary chemoradiation with cisplatin versus cetuximab for locally advanced head and neck cancer: a retrospective cohort study . Experimental Hematology & Oncology . 9 . 19 . 2020 . 32775042 . 7409407 . 10.1186/s40164-020-00175-1 . free .
  7. 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 . Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial . Lancet . 393 . 10166 . 40–50 . January 2019 . 30449625 . 6541928 . 10.1016/S0140-6736(18)32779-X .
  8. 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 . Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial . Lancet . 393 . 10166 . 51–60 . January 2019 . 30449623 . 6319250 . 10.1016/S0140-6736(18)32752-1 .
  9. Web site: Archived copy . 17 August 2024 . 17 August 2024 . https://web.archive.org/web/20240817060527/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/125084s0167ltr.pdf . live .
  10. Web site: Erbitux (cetuximab) Solution for intravenous infusion . DailyMed . 17 August 2024.
  11. Nguyen A, Hoang V, Laquer V, Kelly KM . Angiogenesis in cutaneous disease: part I . Journal of the American Academy of Dermatology . 61 . 6 . 921–42; quiz 943–4 . December 2009 . 19925924 . 10.1016/j.jaad.2009.05.052 . 2618247 . 17 May 2023 . 17 August 2024 . https://web.archive.org/web/20240817052851/https://escholarship.org/uc/item/5p17d7d9 . live .
  12. 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
  13. Berg EA, Platts-Mills TA, Commins SP . Drug allergens and food--the cetuximab and galactose-α-1,3-galactose story . Annals of Allergy, Asthma & Immunology . 112 . 2 . 97–101 . February 2014 . 24468247 . 3964477 . 10.1016/j.anai.2013.11.014 .
  14. 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 . Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose . The New England Journal of Medicine . 358 . 11 . 1109–1117 . March 2008 . 18337601 . 2361129 . 10.1056/NEJMoa074943 .
  15. 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 . Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer . The New England Journal of Medicine . 360 . 14 . 1408–1417 . April 2009 . 19339720 . 10.1056/NEJMoa0805019 . free .
  16. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH . 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 . European Journal of Cancer . 48 . 10 . 1466–1475 . July 2012 . 22446022 . 10.1016/j.ejca.2012.02.057 . free .
  17. Web site: Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations . 2010-01-11 . U.S. Food and Drug Administration (FDA) . 2019-12-16 . 2016-10-24 . https://web.archive.org/web/20161024005434/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm172905.htm . dead .
  18. 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 . Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab . JAMA . 304 . 16 . 1812–1820 . October 2010 . 20978259 . 10.1001/jama.2010.1535 . free .
  19. McFall T, Diedrich JK, Mengistu M, Littlechild SL, Paskvan KV, Sisk-Hackworth L, Moresco JJ, Shaw AS, Stites EC . A systems mechanism for KRAS mutant allele-specific responses to targeted therapy . Science Signaling . 12 . 600 . 8288 . September 2019 . 31551296 . 6864030 . 10.1126/scisignal.aaw8288 .
  20. Rabara D, Tran TH, Dharmaiah S, Stephens RM, McCormick F, Simanshu DK, Holderfield M . KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis . Proceedings of the National Academy of Sciences of the United States of America . 116 . 44 . 22122–22131 . October 2019 . 31611389 . 6825300 . 10.1073/pnas.1908353116 . free . 2019PNAS..11622122R .
  21. Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M . Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice . Journal of the National Cancer Institute . 80 . 20 . 1605–1611 . December 1988 . 3193478 . 10.1093/jnci/80.20.1605 .
  22. Web site: Yeda Research and Development Company Ltd . Technology Transfer Company of the Weizmann Institute of Science . 2013-01-05 . https://web.archive.org/web/20161204093338/http://www.yedarnd.com/ . 2016-12-04 .
  23. Groombridge N, Gearing BP . 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. . The Federal Lawyer . 51–55 . February 2008 . https://web.archive.org/web/20090903012733/http://www.yedarnd.com/images/pics/UserImages/Practical_Lessons%20from%20a%20Made%20for%20TV%20Patent%20Litigation.pdf . 2009-09-03 .
  24. US . 6217866 . patent . Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same . 2001-04-17 . 1995-06-07 . Sela M, Pirak E, Hurwitz E . Yeda Research & Development .
  25. Web site: Court ruling on Yeda vs Aventis/Imclone case . 2012-05-25 . https://web.archive.org/web/20110927101421/http://www.nysd.uscourts.gov/rulings/03CV08484_opinion_091806.pdf . 2011-09-27 .
  26. Web site: Yeda Research v. Imclone Systems, et al . 2015-08-30 . https://web.archive.org/web/20151120002423/http://www.legalmetric.com/cases/patent/nysd/nysd_103cv08484.html . 2015-11-20 .
  27. News: ImClone goes up against patent dispute . 2006-09-14 . USA Today . 2017-08-25 . 2008-02-02 . https://web.archive.org/web/20080202053326/http://www.usatoday.com/money/industries/health/drugs/2006-09-14-imclone-usat_x.htm . live .
  28. Web site: Eli Lilly and Company Form 10-K Annual Report 2013 . 2014-09-22 . 2017-05-04 . https://web.archive.org/web/20170504013929/https://investor.lilly.com/financials.cfm . live .
  29. Schrag D . The price tag on progress--chemotherapy for colorectal cancer . The New England Journal of Medicine . 351 . 4 . 317–319 . July 2004 . 15269308 . 10.1056/NEJMp048143 .
  30. Web site: Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013 . 2021-07-06 . 2016-03-06 . https://web.archive.org/web/20160306161818/http://in.reuters.com/article/us-erbitux-avastin-idINBRE95006O20130601?goback=.gde_1008637_member_245962179 . dead .
  31. Web site: Top 10 best-selling cancer drugs of 2013; May 29, 2014 . September 20, 2014 . April 13, 2016 . https://web.archive.org/web/20160413234945/http://www.fiercepharma.com/special-reports/top-10-best-selling-cancer-drugs-2013 . live .
  32. Douez E, D'Atri V, Guillarme D, Antier D, Guerriaud M, Beck A, Watier H, Foucault-Fruchard L . Why is there no biosimilar of Erbitux? . Journal of Pharmaceutical and Biomedical Analysis . 234 . 115544 . September 2023 . 37418870 . 10.1016/j.jpba.2023.115544 . free . doi .
  33. News: MARTHA STEWART'S SENTENCE: THE OVERVIEW; 5 Months in Jail, and Stewart Vows, 'I'll Be Back' . The New York Times . 17 July 2004 . 2 June 2022 . 17 August 2024 . 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 . live .
  34. News: Bennett C . 'HALF' LIFE OF MARTHA CONVICT . New York Post . 19 August 2008 . 2 June 2022 . 17 August 2024 . https://web.archive.org/web/20240817052809/https://nypost.com/2008/08/19/half-life-of-martha-convict/ . live .
  35. Li K, Li J . Current Molecular Targeted Therapy in Advanced Gastric Cancer: A Comprehensive Review of Therapeutic Mechanism, Clinical Trials, and Practical Application . Gastroenterology Research and Practice . 2016 . 4105615 . 2016 . 26880889 . 4736909 . 10.1155/2016/4105615 . free .
  36. 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 . 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 . The Lancet. Oncology . 21 . 3 . 398–411 . March 2020 . 32014119 . 7052737 . 10.1016/S1470-2045(19)30798-3 .
  37. Web site: Cetuximab for the Treatment of Advanced Unresectable or Metastatic Chordoma . June 2022 . U.S. National Institutes of Health . 4 September 2022 . 17 August 2024 . https://web.archive.org/web/20240817052823/https://clinicaltrials.gov/study/NCT05041127 . live .

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