Cetuximab
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Trade names | Erbitux |
AHFS/Drugs.com | Monograph |
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Intravenous | |
ATC code | |
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Pharmacokinetic data | |
Elimination half-life | 114 hrs |
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Chemical and physical data | |
Formula | C6484H10042N1732O2023S36 |
Molar mass | 145781.92 g·mol−1 |
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Cetuximab, sold under the brand name Erbitux, is an
In July 2009, the U.S. Food and Drug Administration (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).[4] This was the first genetic test to guide treatment of cancer.[5] In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the therascreen KRAS test.[6]
Medical uses
In the US, cetuximab is
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.[3]
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.[5]
Head and neck cancer
Cetuximab was approved by the US
Side effects
One of the more serious side effects of cetuximab therapy is the incidence of
Further severe infusion reactions include but are not limited to: fevers, chills,
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.[14][15]
Mechanism of action
Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR.[15]
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.[16][17]
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.[4]
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.[medical citation needed] Around 65% of mCRC patients have the KRAS wild-type gene.[medical citation needed]
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.
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.[28]
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.[28]
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
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.[32] However biosimilars of Erbitux are not expected until 2018.[33]
As of 2014, biosimilars of cetuximab were in development by several companies.[34][35]
Insider trading
Cetuximab failed to get FDA approval in 2001, which caused the stock price of the developer
Research
The efficacy of cetuximab was explored in a clinical trial of advanced
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.[39]
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.[40]
References
- FDA. Retrieved 22 Oct 2023.
- ^ a b c d "Erbitux- cetuximab solution". DailyMed. 27 September 2021. Retrieved 2 June 2022.
- ^ a b "Erbitux EPAR". European Medicines Agency. 17 September 2018. Retrieved 2 June 2022.
- ^ a b "Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations". U.S. Food and Drug Administration (FDA). 2010-01-11.
- ^ PMID 18946069.
- ^ "Therascreen KRAS RGQ PCR Kit – P110030". Device Approvals and Clearances. U.S. Food and Drug Administration (FDA). 2012-07-06.
- ^ "Cetuximab Beneficial in Head and Neck Cancer". Cancer.gov National Cancer Institute. Archived from the original on 2010-12-21. Retrieved 2013-04-13.
- PMID 26712222.
- PMID 32775042.
- PMID 30449625.
- PMID 30449623.
- S2CID 2618247.
- ^ 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
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- ^ PMID 18337601.
- PMID 19339720.
- PMID 22446022.
- PMID 20978259.
- PMID 31551296.
- PMID 31611389.
- PMID 3193478.
- ^ "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
- ^ 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.
- ^ 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
- ^ "Court ruling on Yeda vs Aventis/Imclone case" (PDF). Archived from the original (PDF) on 2011-09-27. Retrieved 2012-05-25.
- ^ "Yeda Research v. Imclone Systems, et al". Archived from the original on 2015-11-20. Retrieved 2015-08-30.
- ^ "ImClone goes up against patent dispute". USA Today. 2006-09-14.
- ^ a b Eli Lilly and Company Form 10-K Annual Report 2013
- PMID 15269308.
- ^ "Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013". Archived from the original on 2016-03-06. Retrieved 2021-07-06.
- ^ Top 10 best-selling cancer drugs of 2013; May 29, 2014
- ^ Bristol-Myers Squibb Company 2013 Form 10-K
- ^ Merck Serono Investor & Analyst Day 2014 – Belen Garijo's presentation – Slide 41. 18 Sept 2014
- ^ Generics and Biosimilars Initiative (GaBI) – Biosimilars of cetuximab – 14/08/2014
- ^ Torrent Pharma, Reliance Life sign licensing agreement for biosimilars
- ^ "MARTHA STEWART'S SENTENCE: THE OVERVIEW; 5 Months in Jail, and Stewart Vows, 'I'll Be Back'". The New York Times. 17 July 2004. Retrieved 2 June 2022.
- ^ Bennett C (19 August 2008). "'HALF' LIFE OF MARTHA CONVICT". New York Post. Retrieved 2 June 2022.
- PMID 26880889.
- PMID 32014119.
- ^ "Cetuximab for the Treatment of Advanced Unresectable or Metastatic Chordoma". U.S. National Institutes of Health. June 2022.
External links
- "Cetuximab". Drug Information Portal. U.S. National Library of Medicine.
- "Information on Cetuximab (marketed as Erbitux)". U.S. Food and Drug Administration (FDA). 9 July 2015.