Cetuximab

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Cetuximab
Cetuximab.png
Monoclonal antibody
Type Whole antibody
Source Chimeric (mouse/human)
Target EGF receptor
Clinical data
Trade names Erbitux
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 114 hrs
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
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 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]

Contents

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 indicated for 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]

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 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 patients who have had prior platinum-based therapy. [7] 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. [8] However, subsequent studies [9] and clinical trials (NRG Oncology RTOG 1016 [10] and De-ESCALaTE HPV [11] ) suggested cetuximab was significantly inferior in overall and progression-free survival, when compared with cisplatin.

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. [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. [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. [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

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 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. [36] [37]

Research

The efficacy of cetuximab was explored in a clinical trial of advanced gastric cancer published in 2013; cetuximab showed no survival benefit. [38]

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]

Related Research Articles

ImClone Systems Incorporated was a biopharmaceutical company dedicated to developing biologic medicines in the area of oncology. It was founded in 1984 and had its corporate headquarters in Bridgewater, New Jersey, and its research headquarters in New York City. On October 6, 2008, it accepted a $6.5 billion acquisition offer from Eli Lilly and Company, and became a fully-owned subsidiary of Eli Lilly and Company on November 24, 2008. Prior to the acquisition, it was traded on the NASDAQ stock exchange under the symbol IMCL. Imclone lost its separate identity in 2014 when its former ImClone research and manufacturing sites were renamed Eli Lilly and Company.

<span class="mw-page-title-main">Trastuzumab</span> Medication

Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication. Trastuzumab is given by slow injection into a vein and injection just under the skin.

Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Non-small-cell lung cancer</span> Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor.

<span class="mw-page-title-main">KRAS</span> Protein-coding gene in humans

KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Matuzumab is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was developed at the Wistar Institute in Philadelphia, Pennsylvania

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

<span class="mw-page-title-main">Brigatinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

MM-151 is an oligoclonal mixture of fully human monoclonal antibodies, which binds multiple parts of the EGFR molecule It has started clinical trials in patients with RAS wild-type colorectal cancers (CRCs) that were resistant to other anti-EGFR therapies. It is intended to overcome the problem of cancers becoming resistant to monoclonal antibody therapies.

Abituzumab is a humanized IgG2 monoclonal antibody (mAb) targeted at CD51 currently in development by Merck KGaA Darmstadt, Germany in an attempt to prevent bone lesion metastases in castration-resistant prostate cancer.

<span class="mw-page-title-main">Sotorasib</span> Chemical compound

Sotorasib, sold under the brand names Lumakras and Lumykras, is an anti-cancer medication used to treat non-small-cell lung cancer. It targets a specific mutation, G12C, in the protein K-Ras encoded by gene KRAS which is responsible for various forms of cancer. Sotorasib is an inhibitor of the RAS GTPase family.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

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 Oct 2023.
  2. 1 2 3 4 "Erbitux- cetuximab solution". DailyMed. 27 September 2021. Retrieved 2 June 2022.
  3. 1 2 "Erbitux EPAR". European Medicines Agency . 17 September 2018. Retrieved 2 June 2022.
  4. 1 2 "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.
  5. 1 2 Messersmith WA, Ahnen DJ (October 2008). "Targeting EGFR in colorectal cancer". The New England Journal of Medicine. 359 (17): 1834–1836. doi:10.1056/NEJMe0806778. PMID   18946069.
  6. ↑ "Therascreen KRAS RGQ PCR Kit – P110030". Device Approvals and Clearances. U.S. Food and Drug Administration (FDA). 2012-07-06.
  7. ↑ "Cetuximab Beneficial in Head and Neck Cancer". Cancer.gov National Cancer Institute. Archived from the original on 2010-12-21. Retrieved 2013-04-13.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  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.
  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. 1 2 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.
  16. ↑ Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. (April 2009). "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer". The New England Journal of Medicine. 360 (14): 1408–1417. doi: 10.1056/NEJMoa0805019 . PMID   19339720.
  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. ↑ 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.
  19. ↑ 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.
  20. ↑ Rabara D, Tran TH, Dharmaiah S, Stephens RM, McCormick F, Simanshu DK, Holderfield M (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.
  21. ↑ 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.
  22. ↑ "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
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  24. ↑ USpatent 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
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  28. 1 2 Eli Lilly and Company Form 10-K Annual Report 2013
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  31. ↑ Top 10 best-selling cancer drugs of 2013; May 29, 2014
  32. ↑ Bristol-Myers Squibb Company 2013 Form 10-K
  33. ↑ Merck Serono Investor & Analyst Day 2014 – Belen Garijo's presentation – Slide 41. 18 Sept 2014
  34. ↑ Generics and Biosimilars Initiative (GaBI) – Biosimilars of cetuximab – 14/08/2014
  35. ↑ Torrent Pharma, Reliance Life sign licensing agreement for biosimilars
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  38. ↑ 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.
  39. ↑ 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.
  40. ↑ "Cetuximab for the Treatment of Advanced Unresectable or Metastatic Chordoma". U.S. National Institutes of Health. June 2022.
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