Cetuximab

Cetuximab
Monoclonal antibody
TypeWhole antibody
SourceChimeric (mouse/human)
TargetEGF receptor
Clinical data
Trade namesErbitux
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
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
 ☒NcheckY (what is this?)  (verify)

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.[2] Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion.[2]

Cetuximab was approved for medical use in the United States in 2004.[4]

Medical uses

In the US, cetuximab is indicated for the treatment of head and neck cancer and colorectal cancer.[2]

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]

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.[5] 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.[6] However, subsequent studies[7] and clinical trials (NRG Oncology RTOG 1016[8] and De-ESCALaTE HPV[9]) 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.[10][11]

Side effects

One of the more serious side effects of cetuximab therapy is the incidence of acne-like rash. It is generally reversible.[12]

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.[13]

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.[18]

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).[19] 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.[20][21]

History

Observations on EGFR inhibition were published in 1988.[22] Yeda Research, on behalf of the Weizmann Institute of Science in Israel,[23] challenged the Aventis-owned patent,[24] 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.[25] 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.[26][27][28]

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.[29]

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.[29]

Economics

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

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.[31]

Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion.[32]

Biosimilars

See also: Biosimilars

As of 2023, there are no biosimilars of cetuximab.[33]

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.[34][35]

Research

The efficacy of cetuximab was explored in a clinical trial of advanced gastric cancer published in 2013; cetuximab showed no survival benefit.[36]

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.[37]

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.[38]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ a b c d "Erbitux- cetuximab solution". DailyMed. 27 September 2021. Archived from the original on 20 October 2021. Retrieved 2 June 2022.
  3. ^ a b "Erbitux EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 14 May 2021. Retrieved 2 June 2022.
  4. ^ "Drug Approval Package: Erbitux BLA 125084". accessdata.fda.gov. 13 September 2004. Retrieved 17 August 2024.
  5. ^ "Cetuximab Beneficial in Head and Neck Cancer". Cancer.gov National Cancer Institute. Archived from the original on 21 December 2010. Retrieved 13 April 2013.
  6. ^ Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, et al. (April 2016). "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. doi:10.1200/JCO.2015.62.5970. PMC 5070577. PMID 26712222.
  7. ^ Jeong IS, Mo H, Nguyen A, Chong EG, Tsai HH, Moyers J, et al. (2020). "Primary chemoradiation with cisplatin versus cetuximab for locally advanced head and neck cancer: a retrospective cohort study". Experimental Hematology & Oncology. 9: 19. doi:10.1186/s40164-020-00175-1. PMC 7409407. PMID 32775042.
  8. ^ Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, et al. (January 2019). "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. doi:10.1016/S0140-6736(18)32779-X. PMC 6541928. PMID 30449625.
  9. ^ Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. (January 2019). "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. doi:10.1016/S0140-6736(18)32752-1. PMC 6319250. PMID 30449623.
  10. ^ "Archived copy" (PDF). Archived (PDF) from the original on 17 August 2024. Retrieved 17 August 2024.{{cite web}}: CS1 maint: archived copy as title (link)
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  12. ^ Nguyen A, Hoang V, Laquer V, Kelly KM (December 2009). "Angiogenesis in cutaneous disease: part I". Journal of the American Academy of Dermatology. 61 (6): 921–42, quiz 943–4. doi:10.1016/j.jaad.2009.05.052. PMID 19925924. S2CID 2618247. Archived from the original on 17 August 2024. Retrieved 17 May 2023.
  13. ^ 8. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically
  14. ^ Berg EA, Platts-Mills TA, Commins SP (February 2014). "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.
  15. ^ a b Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. (March 2008). "Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose". The New England Journal of Medicine. 358 (11): 1109–1117. doi:10.1056/NEJMoa074943. PMC 2361129. PMID 18337601.
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  17. ^ Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, et al. (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". European Journal of Cancer. 48 (10): 1466–1475. doi:10.1016/j.ejca.2012.02.057. PMID 22446022.
  18. ^ "Class Labeling Changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS Mutations". U.S. Food and Drug Administration (FDA). 11 January 2010. Archived from the original on 24 October 2016. Retrieved 16 December 2019.
  19. ^ De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, et al. (October 2010). "Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab". JAMA. 304 (16): 1812–1820. doi:10.1001/jama.2010.1535. PMID 20978259.
  20. ^ McFall T, Diedrich JK, Mengistu M, Littlechild SL, Paskvan KV, Sisk-Hackworth L, et al. (September 2019). "A systems mechanism for KRAS mutant allele-specific responses to targeted therapy". Science Signaling. 12 (600): 8288. doi:10.1126/scisignal.aaw8288. PMC 6864030. PMID 31551296.
  21. ^ Rabara D, Tran TH, Dharmaiah S, Stephens RM, McCormick F, Simanshu DK, et al. (October 2019). "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. Bibcode:2019PNAS..11622122R. doi:10.1073/pnas.1908353116. PMC 6825300. PMID 31611389.
  22. ^ Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M (December 1988). "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. doi:10.1093/jnci/80.20.1605. PMID 3193478.
  23. ^ "Yeda Research and Development Company Ltd". Archived from the original on 4 December 2016. Retrieved 5 January 2013. Technology Transfer Company of the Weizmann Institute of Science
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  25. ^ 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 
  26. ^ "Court ruling on Yeda vs Aventis/Imclone case" (PDF). Archived from the original (PDF) on 27 September 2011. Retrieved 25 May 2012.
  27. ^ "Yeda Research v. Imclone Systems, et al". Archived from the original on 20 November 2015. Retrieved 30 August 2015.
  28. ^ "ImClone goes up against patent dispute". USA Today. 14 September 2006. Archived from the original on 2 February 2008. Retrieved 25 August 2017.
  29. ^ a b "Eli Lilly and Company Form 10-K Annual Report 2013". Archived from the original on 4 May 2017. Retrieved 22 September 2014.
  30. ^ Schrag D (July 2004). "The price tag on progress--chemotherapy for colorectal cancer". The New England Journal of Medicine. 351 (4): 317–319. doi:10.1056/NEJMp048143. PMID 15269308.
  31. ^ "Merck KGaA's Erbitux beats Avastin in bowel cancer trial, Reuters, Jun 1 2013". Archived from the original on 6 March 2016. Retrieved 6 July 2021.
  32. ^ "Top 10 best-selling cancer drugs of 2013; May 29, 2014". Archived from the original on 13 April 2016. Retrieved 20 September 2014.
  33. ^ Douez E, D'Atri V, Guillarme D, Antier D, Guerriaud M, Beck A, et al. (September 2023). "Why is there no biosimilar of Erbitux?". Journal of Pharmaceutical and Biomedical Analysis. 234: 115544. doi:10.1016/j.jpba.2023.115544. PMID 37418870.
  34. ^ "MARTHA STEWART'S SENTENCE: THE OVERVIEW; 5 Months in Jail, and Stewart Vows, 'I'll Be Back'". The New York Times. 17 July 2004. Archived from the original on 17 August 2024. Retrieved 2 June 2022.
  35. ^ Bennett C (19 August 2008). "'HALF' LIFE OF MARTHA CONVICT". New York Post. Archived from the original on 17 August 2024. Retrieved 2 June 2022.
  36. ^ Li K, Li J (2016). "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. doi:10.1155/2016/4105615. PMC 4736909. PMID 26880889.
  37. ^ Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, et al. (March 2020). "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. doi:10.1016/S1470-2045(19)30798-3. PMC 7052737. PMID 32014119.
  38. ^ "Cetuximab for the Treatment of Advanced Unresectable or Metastatic Chordoma". U.S. National Institutes of Health. June 2022. Archived from the original on 17 August 2024. Retrieved 4 September 2022.

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