Related Pages Head and Neck Cancer Home Page 1 NCI's gateway for information about head and neck cancer. Colon and Rectal Cancer Home Page 2 NCI's gateway for information about colon and rectal cancer. Drug Information Summaries 3 NCI's drug information summaries provide consumer-friendly information about certain drugs that are approved by the U.S. Food and Drug Administration (FDA) to treat cancer or conditions related to cancer.

Brand name(s): Erbitux®

• Approved for head and neck cancer
• Approved for colorectal cancer

Full prescribing information ⁴ is available, including clinical trial information, safety, dosing, drug-drug interaction, and contraindications.

Head and Neck Cancer

On March 1, 2006, the U.S. Food and Drug Administration granted approval to cetuximab (Erbitux®, made by ImClone Systems, Inc.) for use in combination with radiation therapy (RT) for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN) or as a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed.

This approval is based on a statistically significant improvement in overall survival and duration of locoregional disease control for RT plus cetuximab when compared to RT alone. Evidence of cetuximab safety and efficacy is also supported by demonstration of durable objective tumor responses with cetuximab when administered as a single-agent in second- or third-line treatment of advanced SCCHN.

The safety and efficacy of cetuximab in combination with RT were demonstrated in a phase III randomized trial of 424 patients with stage III/IV SCC of the oropharynx, hypopharynx, or larynx who had no prior therapy. Patients were randomized to receive either cetuximab plus RT (211 patients) or RT alone (213 patients).

Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly for the duration of RT (six to seven weeks), starting one week before RT. RT was administered for six to seven weeks as once daily, twice daily or concomitant boost.

The median survival time was 49 months on the cetuximab plus RT versus 29.3 months observed in patients receiving RT alone [p=0.03, stratified log-rank test; hazard ratio 0.74, (95 percent CI 90.56, 0.97)]. The median duration of locoregional control was 24.4 months in patients receiving cetuximab plus RT versus 14.9 months for those receiving RT alone [p=0.005, stratified log-rank test; hazard ratio 0.68, 95 percent CI (0.52, 0.89)]. The observed effect was primarily confined to patients enrolled in sites in the United States.

Additional data were derived from a single-arm trial of cetuximab monotherapy in103 patients with recurrent or metastatic SCCHN after failure of platinum-based therapy. Eighty percent had metastatic disease. Patients received cetuximab as a 400 mg/m2 loading dose, followed by 250 mg/m2 weekly. The objective response rate of cetuximab monotherapy was 12.6 percent (95 percent CI 7 percent to 21 percent). Median response duration was 5.8 months (95 percent CI 2.9; 5.8).

The most common adverse events reported for both treatment arms were mucositis and radiation dermatitis. The incidence of serious mucositis, radiation dermatitis and allergic/anaphylatoid reaction were > 2 percent higher in the RT + cetuximab arm when compared with RT alone. The following serious adverse reactions, some with fatal outcome were observed in the cetuximab plus RT arm: infusion reactions, cardiopulmonary arrest and/or sudden death and acneform rash.

The overall incidence of late radiation toxicity (any grade) was higher in the cetuximab plus RT arm compared with RT alone. However, the incidence of grade 3 or 4 late radiation toxicities were generally similar between the two treatment groups.

Death and serious cardiotoxicity were observed in a single arm trial combining cisplatin with cetuximab and RT conducted in patients with locally advanced squamous cell cancer of the head neck. The cetuximab, RT and cisplatin combination should be reserved for controlled clinical trials where toxicity can be clearly evaluated.

Adverse events associated with cetuximab monotherapy in patients with SCCHN were generally consistent with the adverse reactions previously described for cetuximab. The following serious adverse reactions, some with fatal outcomes, have been reported in the cetuximab safety data base: infusion reactions, interstitial lung disease, acneform rash and hypomagnesemia.

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Colorectal Cancer

On February 12, 2004, the U.S. Food and Drug Administration approved cetuximab (Erbitux®, made by Imclone Systems, Inc.), a monoclonal antibody directed against the epidermal growth factor receptor (EGFR). Cetuximab is approved for use, in combination with irinotecan, for the treatment of EGFR-expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy.

Cetuximab is also approved for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy.

Cetuximab is a recombinant, human/mouse chimeric IgG1 monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor–alpha.

Binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over-expression of EGFR is also detected in many human cancers including those of the colon and rectum.

The recommended dose of cetuximab, in combination with irinotecan or as monotherapy, is 400 mg/m2 as an initial loading dose (first infusion only) administered as a 120-minute IV infusion. The recommended weekly maintenance dose is 250 mg/m2 infused over 60 minutes.

Premedication with an H1 antagonist is recommended. Appropriate medical resources for the treatment of severe infusion reactions should be available during cetuximab infusions. The rate of cetuximab infusion should be reduced for mild or moderate infusion reactions; cetuximab should be discontinued for severe infusion reactions. Dose reductions are also recommended for moderate or severe skin toxicity.

The data establishing the efficacy and safety of cetuximab were derived mainly from the results of a multicenter, randomized, controlled clinical trial conducted in 329 patients; patients were randomized to receive either cetuximab plus irinotecan (218 patients) or cetuximab monotherapy (111 patients).

Supporting data were derived from an open-label, single-arm trial (138 patients) of cetuximab plus irinotecan and an open-label single-arm trial (57 patients) of cetuximab as a single agent. All studies enrolled patients with EGFR-expressing (75-82 percent of those screened were positive), recurrent, metastatic colorectal cancer. All patients had received prior irinotecan; two-thirds of the patients in the randomized study and half of those in the supportive study had progressed during or within 30 days of receiving an adequate course of irinotecan.

In the randomized trial, 38 percent had also received prior oxaliplatin. Determination of clinical benefit was based on evidence of durable responses without evidence of an effect on survival. In the randomized trial, the overall response rate was 23 percent with a median duration of response of 5.7 months in the cetuximab plus irinotecan arm. The overall response rate was 12 percent with a median duration of response of 4.1 months in the cetuximab monotherapy arm.

The median time to progression was significantly longer for patients receiving combination therapy (4.1 vs. 1.5 months). Comparable results were observed in the single arm studies of cetuximab plus irinotecan (15 percent ORR, 6.5 months median response duration) and cetuximab monotherapy (9 percent ORR, 1.4 months median response duration).

The most serious adverse reactions observed in clinical trials of cetuximab, alone or in combination with irinotecan, were infusion reactions (3 percent), dermatologic toxicity (1 percent), interstitial lung disease (0.5 percent), fever (5 percent), sepsis (3 percent); renal dysfunction (2 percent), pulmonary embolism (1 percent), dehydration (5 percent in patients receiving cetuximab plus irinotecan; 2 percent in patients receiving cetuximab monotherapy), and diarrhea (6 percent in patients receiving cetuximab plus irinotecan, 0 percent in patients receiving cetuximab monotherapy).

Thirty-seven (10 percent) patients receiving cetuximab plus irinotecan and 14 (5 percent) patients receiving cetuximab monotherapy discontinued treatment primarily because of adverse events.

The most common adverse events seen in 354 patients receiving cetuximab plus irinotecan were acneform rash (88 percent), asthenia/malaise (73 percent), diarrhea (72 percent), nausea (55 percent), abdominal pain (45 percent), and vomiting (41 percent).

The most common adverse events seen in 279 patients receiving cetuximab monotherapy were acneform rash (90 percent), asthenia/malaise (49 percent), fever (33 percent), nausea (29 percent), constipation (28 percent), and diarrhea (28 percent).

On October 2, 2007, the FDA expanded labeling and granted regular approval for single-agent cetuximab for the treatment of patients with EGFR-expressing metastatic colorectal cancer (mCRC) after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens. Cetuximab was initially approved in 2004 under accelerated approval regulations and the study described below verifies the clinical benefit of single-agent cetuximab in this patient population.

The study supporting conversion to regular approval was an open-label, multinational study conducted by the NCI-Canada (NCIC) in patients with EGFR-expressing, progressive mCRC following both irinotecan- and oxaliplatin-containing regimens.

Five hundred seventy-two patients were randomized (1:1) to best supportive palliative care (BSC) or palliative care plus cetuximab administered as an intravenous infusion of 400 mg/m2 on the first dose, then 250 mg/m2 weekly until disease progression. Patients randomized to cetuximab demonstrated a statistically significant improvement in overall survival (OS) compared to those randomized to best supportive care (median OS: 6.1 vs. 4.6 months; hazard ratio 0.766, p=0.0048, stratified log-rank test). All documented tumor responses (evaluated centrally by NCIC) occurred in patients randomized to cetuximab (6.6 percent); the median response duration was 5.5 months and all were partial responses.

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Glossary Terms

In medicine, a substance that stops the action or effect of another substance. For example, a drug that blocks the stimulating effect of estrogen on a tumor cell is called an estrogen receptor antagonist.

A type of cell death in which a series of molecular steps in a cell leads to its death. This is the body’s normal way of getting rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death.

Weakness; lack of energy and strength.

Having to do with the heart and lungs.

Toxicity that affects the heart.

A monoclonal antibody used to treat certain types of head and neck cancer, and colorectal cancer that has spread to other parts of the body. It is also being studied in the treatment of other types of cancer. Monoclonal antibodies are made in the laboratory and can locate and bind to cancer cells. Cetuximab binds to the epidermal growth factor receptor (EGFR), which is found on the surface of some types of cancer cells. Also called Erbitux.

A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all.

Inflammation of the skin.

A block in an artery caused by blood clots or other substances, such as fat globules, infected tissue, or cancer cells.

The protein found on the surface of some cells and to which epidermal growth factor binds, causing the cells to divide. It is found at abnormally high levels on the surface of many types of cancer cells, so these cells may divide excessively in the presence of epidermal growth factor. Also called EGFR, ErbB1, and HER1.

Refers to the cells that line the internal and external surfaces of the body.

The bottom part of the throat. Cancer of the hypopharynx is also known as hypopharyngeal cancer.

A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion.

The active ingredient in a drug used alone or in combination with other drugs to treat colon cancer or rectal cancer that has spread to other parts of the body or has come back after treatment with fluorouracil. It is also being studied in the treatment of other types of cancer. Irinotecan blocks certain enzymes needed for cell division and DNA repair, and it may kill cancer cells. It is a type of topoisomerase inhibitor and a type of camptothecin analog.

The area of the throat containing the vocal cords and used for breathing, swallowing, and talking. Also called voice box.

Cancer that has spread from where it started to nearby tissue or lymph nodes.

A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis.

A statistics term. The middle value in a set of measurements.

The time from either diagnosis or treatment at which half of the patients with a given disease are found to be, or expected to be, still alive. In a clinical trial, median survival time is one way to measure how effective a treatment is. Also called median overall survival and median survival.

A type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. There are many kinds of monoclonal antibodies. Each monoclonal antibody is made to find one substance. Monoclonal antibodies are being used to treat some types of cancer and are being studied in the treatment of other types. They can be used alone or to carry drugs, toxins, or radioactive materials directly to a tumor.

A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth.

A measurable response.

The part of the throat at the back of the mouth behind the oral cavity. It includes the back third of the tongue, the soft palate, the side and back walls of the throat, and the tonsils.

A drug used together with other drugs to treat colorectal cancer that is advanced or has come back. It is also being studied in the treatment of other types of cancer. Oxaliplatin attaches to DNA in cells and may kill cancer cells. It is a type of platinum compound. Also called Eloxatin.

Care given to improve the quality of life of patients who have a serious or life-threatening disease. The goal of palliative care is to prevent or treat as early as possible the symptoms of a disease, side effects caused by treatment of a disease, and psychological, social, and spiritual problems related to a disease or its treatment. Also called comfort care, supportive care, and symptom management.

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

A metal that is an important component of some anticancer drugs, such as cisplatin and carboplatin.

Having to do with the lungs.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

In genetics, describes DNA, proteins, cells, or organisms that are made by combining genetic material from two different sources. Recombinant substances are made in the laboratory and are being studied in the treatment of cancer and for many other uses.

In medicine, describes a disease or condition that does not respond to treatment.

The percentage of patients whose cancer shrinks or disappears after treatment.

The presence of bacteria or their toxins in the blood or tissues.

Cancer that begins in squamous cells, which are thin, flat cells that look like fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

Care given to improve the quality of life of patients who have a serious or life-threatening disease. The goal of supportive care is to prevent or treat as early as possible the symptoms of a disease, side effects caused by treatment of a disease, and psychological, social, and spiritual problems related to a disease or its treatment. Also called comfort care, palliative care, and symptom management.

A measure of time after a disease is diagnosed (or treated) until the disease starts to get worse. Also called TTP.

A substance made by cells that stimulates new blood vessel formation. Also called VEGF.