Cetuximab

Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion that is distributed under the trade name Erbitux in the U.S. and Canada by the drug company Eli Lilly and Co. and outside those countries by the drug company Merck KGaA. In Japan, Merck KGaA, Bristol-Myers Squibb and Eli Lilly have a co-distribution.

Cetuximab
Monoclonal antibody
TypeWhole antibody
SourceChimeric (mouse/human)
TargetEGF receptor
Clinical data
Trade namesErbitux
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
    Routes of
    administration    		intravenous
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Elimination half-life114 hrs
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    Chemical and physical data
    FormulaC6484H10042N1732O2023S36
    Molar mass145781.92 g·mol−1
     NY (what is this?)  (verify)

    In July 2009, the FDA approved cetuximab (Erbitux) for treatment of colon cancer with wild-type KRAS, since it had little or no effect in colorectal tumors harboring a KRAS mutation (this also applied to the EGFR antibody panitumumab).[1] This was the first genetic test to guide treatment of cancer.[2] In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the therascreen KRAS test.[3]

    Cetuximab is approved for K-RAS wild-type metastatic colorectal cancer in the US & Canada (Eli Lilly). In Europe and the rest of the world (Merck KGaA), cetuximab is approved for RAS wild-type metastatic colorectal cancer.

    Medical uses

    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 panitumumab, according to FDA guidelines. Unfortunately, there is evidence that immunohistochemical EGFR receptor testing does not predict response to either cetuximab or panitumumab, so that this has been called a "misleading biomarker" that has nevertheless caused insurers and even health systems to deny payment for EGFR antibody treatment for patients who lack a positive tumor EGFR histochemical test.[2]

    Head and neck cancer

    Cetuximab was approved by the 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 patients who have had prior platinum-based therapy.[4]

    Side effects

    One of the more serious side effects of cetuximab therapy is the incidence of acne-like rash. This rash rarely leads to dose reductions or termination of therapy. It is generally reversible.[5]

    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. Therefore, pretreatment with diphenhydramine (30 to 60) min before administration is standard of care. Other common side effects include photosensitivity, hypomagnesemia due to magnesium wasting, and less commonly pulmonary and cardiac toxicity. [6]

    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.[7][8] The alpha-gal allergy is believed to result from tick bites. Lone star ticks are native to the regions of the US where reactions occurred and were found to be the vector. Cetuximab is produced in the mouse myeloma cell line SP2/0, and contains the alpha-gal oligosaccharide on the Fab portion of the heavy chain.

    Mechanism of action

    Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR.[8]

    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.[9][10][10]

    KRAS mutational analysis is commercially available from a number of laboratories.

    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.[1]

    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.

    History

    Michael Sela, Ester Hurwitz and co-workers published observations on EGFR inhibition in 1988.[11] Yeda Research, on behalf of the Weizmann Institute of Science in Israel,[12] challenged the Aventis-owned patent,[13] 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.[14] 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.[15][16][17]

    Society and culture

    Manufacture
    • 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.[18]

    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.[18]

    Sales

    Cetuximab is given by intravenous therapy and costs up to $30,000 for eight weeks of treatment per patient.[19]

    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.[20]

    Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion.[21]

    Biosimilars
    See also: Biosimilars

    Erbitux had 2013 worldwide sales of US$1.9 billion making it a lucrative target for biosimilars developers. Additionally the patent protection for Erbitux in Europe expired in June 2014, and in the U.S. and in Japan the protection will expire in 2016.[22] However biosimilars of Erbitux are not expected until 2018.[23]

    As of 2014 biosimilars of cetuximab were in development by several companies.[24][25]

    Insider trading
    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.

    Research

    The efficacy of cetuximab was explored in a clinical trial of advanced gastric cancer published in 2013; cetuximab showed no survival benefit.[26]

    A 2020 phase 3 multicentre 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.[27]

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    References
    1. "Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations". U.S. Food and Drug Administration. 2010-01-11.
    2. Messersmith WA, Ahnen DJ (October 2008). "Targeting EGFR in colorectal cancer". N. Engl. J. Med. 359 (17): 1834–36. doi:10.1056/NEJMe0806778. PMID 18946069.
    3. "Therascreen KRAS RGQ PCR Kit – P110030". Device Approvals and Clearances. U.S. Food and Drug Administration. 2012-07-06.
    4. "Cetuximab Beneficial in Head and Neck Cancer". Cancer.gov National Cancer Institute. Archived from the original on 2010-12-21. Retrieved 2013-04-13.
    5. Nguyen A, Hoang V, Laquer V, Kelly KM (December 2009). "Angiogenesis in cutaneous disease: part I" (PDF). J. Am. Acad. Dermatol. 61 (6): 921–42, quiz 943–4. doi:10.1016/j.jaad.2009.05.052. PMID 19925924.
    6. 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
    7. Berg, E. A.; Platts-Mills, T. A.; Commins, S. P. (2013). "Drug allergens and food—the cetuximab and galactose-α-1,3-galactose story". Annals of Allergy, Asthma & Immunology. 112 (2): 97–101. doi:10.1016/j.anai.2013.11.014. PMC 3964477. PMID 24468247.
    8. Chung, Christine H.; Mirakhur, Beloo; Chan, Emily; Le, Quynh-Thu; Berlin, Jordan; Morse, Michael; Murphy, Barbara A.; Satinover, Shama M.; Hosen, Jacob; Mauro, David; Slebos, Robbert J.; Zhou, Qinwei; Gold, Diane; Hatley, Tina; Hicklin, Daniel J.; Platts-Mills, Thomas A.E. (13 March 2008). "Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-α-1,3-Galactose". The New England Journal of Medicine. 358 (11): 1109–17. doi:10.1056/NEJMoa074943. ISSN 0028-4793. PMC 2361129. PMID 18337601.
    9. Van Cutsem E, et al. (April 2009). "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer". N. Engl. J. Med. 360 (14): 1408–17. doi:10.1056/NEJMoa0805019. PMID 19339720.
    10. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH (July 2012). "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". Eur. J. Cancer. 48 (10): 1466–75. doi:10.1016/j.ejca.2012.02.057. PMID 22446022.
    11. Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M (1988-12-21). "Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice". J. Natl. Cancer Inst. 80 (20): 1605–11. doi:10.1093/jnci/80.20.1605. PMID 3193478.
    12. "Yeda Research and Development Company Ltd". Archived from the original on 2016-12-04. Retrieved 2013-01-05. Technology Transfer Company of the Weizmann Institute of Science
    13. Groombridge N, Gearing BP (February 2008). "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" (PDF). The Federal Lawyer: 51–55. Archived from the original (PDF) on 2009-09-03.
    14. US patent 6217866, Sela M, Pirak E, Hurwitz E, "Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same", published 2001-04-17, assigned to Yeda Research & Development
    15. "Court ruling on Yeda vs Aventis/Imclone case" (PDF). Archived from the original (PDF) on 2011-09-27. Retrieved 2012-05-25.
    16. "Archived copy". Archived from the original on 2015-11-20. Retrieved 2015-08-30.CS1 maint: archived copy as title (link)
    17. "ImClone goes up against patent dispute". USA Today. 2006-09-14.
    18. Eli Lilly and Company Form 10-K Annual Report 2013
    19. Schrag D (July 2004). "The price tag on progress – chemotherapy for colorectal cancer". N. Engl. J. Med. 351 (4): 317–19. doi:10.1056/NEJMp048143. PMID 15269308.
    20. Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013
    21. Top 10 best-selling cancer drugs of 2013; May 29, 2014
    22. Bristol-Myers Squibb Company 2013 Form 10-K
    23. Merck Serono Investor & Analyst Day 2014 – Belen Garijo’s presentation – Slide 41. 18 Sept 2014
    24. Generics and Biosimilars Initiative (GaBI) – Biosimilars of cetuximab – 14/08/2014
    25. Torrent Pharma, Reliance Life sign licensing agreement for biosimilars
    26. Li K, Li J (2016). "Current Molecular Targeted Therapy in Advanced Gastric Cancer: A Comprehensive Review of Therapeutic Mechanism, Clinical Trials, and Practical Application". Gastroenterol Res Pract. 2016: 4105615. doi:10.1155/2016/4105615. PMC 4736909. PMID 26880889.
    27. "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". Lancet. Retrieved 5 February 2020.
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