Cetuximab
Encyclopedia
Cetuximab is a chimeric (mouse/human) monoclonal antibody, an epidermal growth factor receptor (EGFR) inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer
and head and neck cancer
.
and Bristol-Myers Squibb, while in the rest of the world distribution is by Merck KGaA. Cetuximab is given by intravenous therapy
and costs up to $30,000 for eight weeks of treatment per patient.
(EGFR)-expressing, KRAS
wild-type metastatic colorectal cancer
(mCRC), in combination with chemotherapy, and as a single agent in patients who have failed oxaliplatin
- and irinotecan
-based therapy and who are intolerant to irinotecan. The positive opinion from the Committee for Medicinal Products for Human Use (CHMP) was received for mCRC 1st line use in May 2008.
Cetuximab (Erbitux) is indicated for the treatment of patients with squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease. The positive CHMP opinion for this indication was received in October 2008.
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
.
There is increasing evidence to support the use of biomarkers in predicting tumor response to treatment, as this allows therapeutic approaches to be tailored or personalized to individual patients and results in improved outcomes and survival. While there remains some scientific controversy on this, assessment for EGFR expression is required for the use of cetuximab (Erbitux) in Colorectal Cancer, but not in Head & Neck Cancer.
Many clinical trials have been conducted to investigate the efficacy of cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and there is increasing evidence to support the use of biomarkers, such as KRAS, to predict tumor response to anti-EGFR therapies. Two large clinical trials of cetuximab, OPUS and CRYSTAL, have recently been published, and have provided further evidence that cetuximab significantly improves response rates and disease free survival rates in mCRC patients with KRAS wild-type tumors.
A study in June 2010 found that Erbitux failed to benefit patients with less advanced (non-metastasized) stages of colorectal cancer http://industry-news.org/2010/06/06/lillys-erbitux-fails-in-study-to-stop-colon-cancer-before-it-has-spread/ with no improvement in survival rates. Adding Erbitux instead increased the side effects of chemotherapy.
Several recent studies showed:
Adding the targeted drug cetuximab to a three-drug chemotherapy regimen for first-line treatment of metastatic colorectal cancer does not improve response rate, progression-free survival or overall survival, researchers reported at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy
A second Phase III study (COIN) of cetuximab in combination with capecitabine and oxaliplatin versus chemotherapy alone in first-line mCRC, did not meet its primary endpoint of overall survival in K-ras wild type patients (17 months vs. 17.9 months; HR 1.038; 95% CI 0.90 - 1.20; p=0.68).
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.
Two landmark studies have evaluated the benefits of cetuximab (Erbitux) in patients with SCCHN in both the locally advanced (Bonner trial) and the recurrent and/or metastatic (EXTREME trial) settings. The EXTREME trial is the first time in 30 years that a Phase III trial has demonstrated a survival benefit in 1st-line recurrent and/or metastatic disease. Erbitux was granted approval by the European Commission in November 2008 for the treatment of 1st-line recurrent and/or metastatic SCCHN based on the results of the EXTREME study.
showed that resistance to cetuximab was likely to be mediated via signalling through the HER2/neu
protein - either through upregulation of protein production or overexpression of the gene. This opens up the possibility that combination therapy with HER2/neu-targeting drugs such as trastuzumab
or lapatinib
may prove effective, although as yet this is unproven.
As well as severe infusion reactions including but not limited to: fevers, chills, rigors, urticaria
, pruritis, rash, hypotension, N/V, HA, bronchospasm, dyspnea, wheezing, angioedema, dizziness, anaphylaxis
, and cardiac arrest. Therefore, pretreatment with diphenhydramine
30-60 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.
gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors that are not mutated.
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.
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. Recent data suggest that around 65% of mCRC patients have the KRAS wild-type gene.
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and head and neck cancer
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
.
Distribution
Cetuximab is manufactured and distributed in North America by ImCloneImClone Systems
ImClone Systems Incorporated is a biopharmaceutical company dedicated to developing biologic medicines in the area of oncology. It was founded in 1984 and is headquartered in New York City. On October 6, 2008, it accepted a $6.5 billion acquisition offer from Eli Lilly and Company, and became a...
and Bristol-Myers Squibb, while in the rest of the world distribution is by Merck KGaA. Cetuximab is given by intravenous therapy
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
and costs up to $30,000 for eight weeks of treatment per patient.
Indications
Cetuximab is indicated for the treatment of patients with epidermal growth factor receptorEpidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(EGFR)-expressing, KRAS
KRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
wild-type metastatic colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
(mCRC), in combination with chemotherapy, and as a single agent in patients who have failed oxaliplatin
Oxaliplatin
Oxaliplatin is a coordination complex that is used in cancer chemotherapy. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups ....
- and irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
-based therapy and who are intolerant to irinotecan. The positive opinion from the Committee for Medicinal Products for Human Use (CHMP) was received for mCRC 1st line use in May 2008.
Cetuximab (Erbitux) is indicated for the treatment of patients with squamous cell carcinoma of the head and neck in combination with platinum-based chemotherapy for the 1st line treatment of recurrent and/or metastatic disease and in combination with radiation therapy for locally advanced disease. The positive CHMP opinion for this indication was received in October 2008.
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
Panitumumab
Panitumumab , formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor ....
.
Biomarkers
In mCRC, biomarkers, including KRAS, are indicative of response to cetuximab (Erbitux). 60% of patients express the KRAS wild-type tumor and data have shown that these patients are significantly more likely to benefit from treatment with cetuximab or a combination of cetuximab plus chemotherapy. Two recent studies demonstrated that patients with KRAS wild-type tumors demonstrated significantly increased response rates and disease free survival when treated with cetuximab and standard chemotherapy (OPUS AND CRYSTAL), compared to patients receiving chemotherapy alone.There is increasing evidence to support the use of biomarkers in predicting tumor response to treatment, as this allows therapeutic approaches to be tailored or personalized to individual patients and results in improved outcomes and survival. While there remains some scientific controversy on this, assessment for EGFR expression is required for the use of cetuximab (Erbitux) in Colorectal Cancer, but not in Head & Neck Cancer.
Colorectal cancer
Cetuximab is indicated for the treatment of patients with EGFR expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy or as a single agent in patients who have failed in oxaliplatin- or irinotecan- base therapy and who are intolerant to irinotecan. While there remains some scientific controversy on this, assessment for EGFR expression is required for use in colorectal cancer, but not in head & neck cancer.Many clinical trials have been conducted to investigate the efficacy of cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) and there is increasing evidence to support the use of biomarkers, such as KRAS, to predict tumor response to anti-EGFR therapies. Two large clinical trials of cetuximab, OPUS and CRYSTAL, have recently been published, and have provided further evidence that cetuximab significantly improves response rates and disease free survival rates in mCRC patients with KRAS wild-type tumors.
A study in June 2010 found that Erbitux failed to benefit patients with less advanced (non-metastasized) stages of colorectal cancer http://industry-news.org/2010/06/06/lillys-erbitux-fails-in-study-to-stop-colon-cancer-before-it-has-spread/ with no improvement in survival rates. Adding Erbitux instead increased the side effects of chemotherapy.
Several recent studies showed:
Adding the targeted drug cetuximab to a three-drug chemotherapy regimen for first-line treatment of metastatic colorectal cancer does not improve response rate, progression-free survival or overall survival, researchers reported at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy
A second Phase III study (COIN) of cetuximab in combination with capecitabine and oxaliplatin versus chemotherapy alone in first-line mCRC, did not meet its primary endpoint of overall survival in K-ras wild type patients (17 months vs. 17.9 months; HR 1.038; 95% CI 0.90 - 1.20; p=0.68).
Head and neck cancer
Cetuximab was approved by the FDAFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in March 2006 for use in combination with radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
for treating squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
of the head and neck (SCCHN
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
) or as a single agent in patients who have had prior platinum-based therapy.
Two landmark studies have evaluated the benefits of cetuximab (Erbitux) in patients with SCCHN in both the locally advanced (Bonner trial) and the recurrent and/or metastatic (EXTREME trial) settings. The EXTREME trial is the first time in 30 years that a Phase III trial has demonstrated a survival benefit in 1st-line recurrent and/or metastatic disease. Erbitux was granted approval by the European Commission in November 2008 for the treatment of 1st-line recurrent and/or metastatic SCCHN based on the results of the EXTREME study.
Resistance
In September 2011, researchers at the Dana-Farber Cancer InstituteDana-Farber Cancer Institute
Dana–Farber Cancer Institute is part of a Comprehensive Cancer Center designated by the National Cancer Institute. It is a major affiliate of Harvard Medical School and is located in the Longwood Medical Area in Boston, Massachusetts.-Overview:...
showed that resistance to cetuximab was likely to be mediated via signalling through the HER2/neu
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
protein - either through upregulation of protein production or overexpression of the gene. This opens up the possibility that combination therapy with HER2/neu-targeting drugs such as trastuzumab
Trastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
or lapatinib
Lapatinib
Lapatinib , used in the form of lapatinib ditosylate, is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. It is used in combination therapy for HER2-positive breast cancer...
may prove effective, although as yet this is unproven.
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.As well as severe infusion reactions including but not limited to: fevers, chills, rigors, urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, pruritis, rash, hypotension, N/V, HA, bronchospasm, dyspnea, wheezing, angioedema, dizziness, anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
, and cardiac arrest. Therefore, pretreatment with diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
30-60 min. before administration is standard of care. Other common side effects include photosensitivity, hypomagnesemia
Hypomagnesemia
Hypomagnesemia is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Usually a serum level less than 0.7 mmol/L is used as reference. The prefix hypo- means low . The middle 'magnes' refers to magnesium...
due to magnesium wasting, and less commonly pulmonary and cardiac toxicity.
KRAS Testing
The KRASKRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors that are not mutated.
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
Panitumumab
Panitumumab , formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor ....
(Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.
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. Recent data suggest that around 65% of mCRC patients have the KRAS wild-type gene.
External links
- FDA Erbitux (cetuximab) Information Page
- Erbitux site from Bristol-Myers Squibb, ImClone Systems, and Merck KGaA
- Anti EGFreceptor monoclonals and small molecules on the web
- HighBeam: Amgen licenses patent after Yeda court win over ImClone
- List of clinical labs performing KRAS mutation analysis
- KRAS information
- KRAS mutation testing information for clinical labs
- http://www.esmo.org/events/milan-2010-congress/news/view.html?tx_ttnews[pointer=4&tx_ttnews[tt_news]=949&tx_ttnews[backPid]=1798&cHash=29a9925fa0]
- http://www.nelm.nhs.uk/en/NeLM-Area/News/2009---September/30/Mixed-results-for-cetuximab-Erbitux-in-first-line-treatment-of-metastatic-colorectal-cancer/