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] In June 2024 together with adagrasib it was approved by the FDA for colorectal cancer. [7] [8]

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. [9] 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. [10] However, subsequent studies [11] and clinical trials (NRG Oncology RTOG 1016 [12] and De-ESCALaTE HPV [13] ) 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. [14]

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. [15]

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. [16] [17]

Mechanism of action

Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR. [17]

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. [18] [19]

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). [20] 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. [21] [22]

History

Observations on EGFR inhibition were published in 1988. [23] Yeda Research, on behalf of the Weizmann Institute of Science in Israel, [24] challenged the Aventis-owned patent, [25] 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. [26] 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. [27] [28] [29]

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. [31]

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. [32]

Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion. [33]

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. [34] However biosimilars of Erbitux are not expected until 2018. [35]

As of 2014, biosimilars of cetuximab were in development by several companies. [36] [37]

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. [38] [39]

Research

The efficacy of cetuximab was explored in a clinical trial of advanced gastric cancer published in 2013; cetuximab showed no survival benefit. [40]

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. [41]

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. [42]

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">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 among others, 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.

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

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer. Adagrasib is an inhibitor of the RAS GTPase family. It is taken by mouth. It is being developed by Mirati Therapeutics.

Amivantamab, sold under the brand name Rybrevant, is a bispecific monoclonal antibody used to treat non-small cell lung cancer. Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

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