Cetuximab (Erbitux; [ImClone, Branchburg, NJ]) is a recombinant human and mouse chimeric monoclonal IgG1 antibody that binds to and inhibits the biologic activity of the human epidermal growth factor receptor (EGFR). This document addresses the indications and criteria for the use of cetuximab in the treatment of oncologic conditions.

For additional information, please refer to the following related document:

• GENE.00014 Analysis of KRAS Status in Metastatic Colorectal Cancer

Medically Necessary: 

Cetuximab is considered medically necessary when the following criteria (A, B and C) are met and the individual meets any of the disease specific indications listed below:

1. The individual has not received prior treatment with panitumumab (Vectibix™, Amgen, Thousand Oaks, CA); AND
2. Cetuximab is not used in combination with anti-VEGF agents (e.g., Bevacizumab); AND
3. Cetuximab may be used for only one line of therapy**.
   
   
   1. Colorectal and Anal Adenocarcinoma*:
      
      Cetuximab is considered medically necessary when criteria A, B and C above are met for treatment of individuals with Stage IV, KRAS-wild type colon*, rectal*, colorectal*, or anal* adenocarcinoma when used as a single agent or as part of combination therapy.
      Notes:  *See definitions of colon, rectal and anal cancer
                 **If cetuximab is recommended as initial therapy, it should not be used in second or subsequent lines  of  therapy
      
      
   2. Head and Neck Cancer:
      
      Cetuximab is considered medically necessary when criteria A, B and C above are met for treatment of individuals with squamous cell carcinoma of the head and neck (SCCHN) when any of the following are also met:
      1. In combination with radiation therapy, for the initial treatment of locally or regionally advanced disease; OR
      2. As a single agent for the treatment of individuals with recurrent or metastatic disease for whom prior platinum-based therapy has failed; OR
      3. Single agent or in combination therapy with or without radiation therapy for any of the following indications:
         1. Unresectable locoregional recurrence or second primary in individuals who have received prior radiation therapy; or
         2. Resectable locoregional recurrence in individuals who have not received prior radiation therapy; or
         3. Distant metastases
            
            
   3. Non-Small Cell Lung Cancer (NSCLC):
      
      Cetuximab is considered medically necessary when criteria A, B and C above are met for individuals with stage IIIB (with malignant pleural effusion) and stage IV non-small cell lung cancer and all of the following are also met:
      1. Cetuximab is used in first-line treatment in combination with cisplatin and vinorelbine; and
      2. No prior chemotherapy or anti-EGFR therapy
      3. EGFR expression (1 positive tumor cell) by immunohistochemistry (IHC); and
      4. No known brain metastases.

Investigational and Not Medically Necessary:

Cetuximab is considered investigational and not medically necessary when the above criteria are not met including, but not limited to use as adjuvant therapy after resection and treatment of squamous cell anal carcinoma.

Cetuximab is considered investigational and not medically necessary when used in combination with other monoclonal antibodies.

Cetuximab is comprised of a murine anti-EGFR antibody with human immunoglobulin-G1 (IgG1) that binds specifically to the extracellular portion of the human epidermal growth factor receptor (EGFR). It is thought to interfere with the growth of cancer cells by blocking the activation of receptor-associated kinases, inducing apoptosis and decreasing the production of vascular endothelial growth factor production. Antibody-dependent cellular cytotoxicity (ADCC) against specific human tumor types may also be mediated by cetuximab. However, the specific mechanism of anti-tumor effect in vivo is unknown (Product Information Label, 2009).

The blockade of the growth factor results in a decrease in tumor growth but does have side effects. Skin rash was the most frequently occurring side effect of cetuximab therapy. Various studies have drawn correlations between the frequency and severity of rash to tumor response rate (Product Information Label, 2009; Zhu, 2007).

Cetuximab was first approved in February 2004, under the U.S. Food and Drug Administration's (FDA) accelerated approval program, which allows the approval of products for cancer and other serious or life-threatening diseases on the basis of early evidence of a product's effectiveness. At that time, cetuximab was approved as a combination treatment with irinotecan for the treatment of metastatic colorectal cancer or alone if the individual is unable to tolerate with irinotecan.

Skin toxicities are side effects for both cetuximab and panitumumab, and are not considered to be an infusion reaction (NCCN, 2010).

Cetuximab is now FDA approved for multiple indications including the treatment of EGFR expressing, metastatic colorectal carcinoma used in combination with irinotecan, in patients who are refractory to irinotecan-based chemotherapy; as a single agent for the treatment of EGFR expressing, metastatic colorectal carcinoma in individuals who are intolerant to irinotecan-based chemotherapy; in combination with radiation therapy, for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck and as a single agent for the treatment of individuals with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed (Product information Label, 2009).

Colorectal and Anal Adenocarcinoma
The medically necessary criteria for excluding the previous use of EGFR monoclonal antibody therapy prior to treatment with cetuximab is based on the selection criteria in the pivotal trial as well as the expert view of medical practitioners practicing in the clinical area of oncology, and who have familiarity with the available evidence at this time. There are currently two FDA approved EGFR inhibitors: cetuximab and panitumumab.  While both are used in the treatment of colorectal cancer, there are no published head-to-head comparisons between the drugs. Additionally, there are no data, nor is there a compelling rationale to support the use of one of these agents after the therapeutic failure of the other and that this practice is not recommended. In addition, there is no published peer reviewed literature to support use of cetuximab in second or subsequent lines of therapy when cetuximab was used as initial therapy.

Squamous cell anal cancer is the most common histologic form of anal cancer. Adenocarcinoma and melanoma of the anal canal represent infrequently occurring subtypes of anal carcinoma. The management of anal adenocarcinoma generally follows management strategies for rectal cancer (NCCN, 2010). The use of cetuximab for treatment of squamous cell anal cancer is not recognized as an off-label indication by NCCN.

The NCCN Anal Carcinoma Clinical Practice Guideline (2010) recommends management of anal adenocarcinoma according to the NCCN Rectal Cancer Clinical Practice Guidelines (2010). Specialty consensus opinion also supports the NCCN recommendations to treat stage IV anal adenocarcinoma similar to stage IV colorectal adenocarcinoma.

In 2010, the National Comprehensive Cancer Network^® (NCCN^®) Clinical Practice Guidelines in Oncology^™ for advanced stage IV colon and rectal adenocarcinoma include offlabel recommendations for cetuximab as a single agent and in combination therapy based on 2A category of evidence and uniform consensus. The offlabel indications are listed in the Position Statement.

There are several recommended off-label uses of cetuximab in combination therapy for metastatic colorectal carcinoma. These regimens include the use of agents such as 5-FU, irinotecan and oxaliplatin. In some situations, the oral formulation of 5-FU, capecitabine, is recommended as equivalent to infused 5-FU. Review of the literature does not support routine use of capecitabine based regimens in combination with cetuximab for metastatic colorectal cancer at this time (NCCN, 2010).

Studies of metastatic colorectal carcinoma treatment have shown there are subsets of patients who are not as responsive to anti-EGFR monoclonal antibodies. To understand the variation, there is ongoing research into the genetic signaling pathways that promote the growth of specific cells. The Kirsten rat sarcoma virus, also known as the KRAS gene, is being analyzed for mutations and correlation of response to anti-EGFR monoclonal antibodies. The desired goal for KRAS status mutation analysis is to identify individuals who would not respond to anti-EGFR monoclonal antibody therapy, thereby saving them the time, expense and unnecessary toxicity of ineffective therapies. 

De Roock and colleagues (2008) conducted a retrospective analysis of 113 individuals with irinotecan-refractory metastatic colorectal carcinoma with available tumor tissue, from four Belgian clinical trials. 102 individuals had completed tumor measurements throughout the clinical trials. The clinical trials utilized cetuximab as monotherapy and in combination therapy. KRAS mutations were detected in 46 of 113 (40.7%) tumors and BRAF V600E mutation was noted in 6 (5.6%) of 107 assessable participants. The combined BRAF and KRAS mutations were not identified in any individual. Five individuals were not assessable prior to the first evaluation. Overall response (OR), including both complete (CR) and partial response (PR), was observed only in the patients with KRAS wild-type (27 of 66 individuals [41%]) compared to individuals with KRAS mutants (0 of 42 patients [0%]). KRAS mutations were identified in 42 of 81 (51.9%) nonresponders, and in 27 OR individuals. There was no statistically significant difference in the median progression-free survival (PFS) in the entire study. However, in the cohort receiving cetuximab in combination therapy, there was a significant median PFS between wild-type KRAS (34 weeks) compared to mutant KRAS (12 weeks; P=0.016). In the entire study population, there was also a significant difference in median OS for KRAS wild-type 43 weeks compared to KRAS mutants 27.3 weeks (P=0.020). The authors concluded "KRAS wild-type is a strong predictor of a significant increase in PFS and OS. However, the KRAS status of a tumor may still fall short as a biomarker, as not all wild-type patients respond or have improved survival and some mutant patients experience long-term disease control."

In addition, a published study (Karapetis, 2008) analyzed KRAS status in tumor samples obtained from 394 of 572 individuals with colorectal cancer who had been randomly assigned to receive cetuximab plus best supportive care, or best supportive care alone. Cetuximab effectiveness was significantly associated with KRAS status; in those with the wild-type version, adding cetuximab to best supportive care alone improved median overall survival (9.5 vs. 4.8 months), hazard ratio for death (0.55), and median progression-free survival (3.7 vs. 1.9 months). Among individuals with mutant KRAS, there was no benefit offered by adding cetuximab to best supportive care. In all individuals receiving best supportive care alone without cetuximab, KRAS status was not significantly associated with overall survival (hazard ratio for death 1.01). An accompanying editorial (Messersmith, 2008) stated it is reasonable to recommend that all individuals with advanced colorectal cancer being considered for anti-EGFR therapy should undergo KRAS testing, and if the mutant gene is detected, anti-EGFR therapy should not be administered.

The data suggest that the metastatic colorectal population with wild-type KRAS mutation status benefited more from cetuximab as compared with those with the activating KRAS mutation. Therefore, analysis of KRAS may be appropriate to facilitate treatment plans. The updated NCCN (2010) guidelines include recommendations for KRAS gene testing for all stage IV colon and rectal disease. Use of cetuximab is indicated for individuals with tumors that express the wild-type KRAS gene. The American Society of Clinical Oncology (ASCO, Allegra, 2009) issued a provisional, consensus clinical opinion based on systematic reviews of literature primarily from phase II and III clinical trials involving individuals with metastatic colorectal cancer. "All individuals with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then individuals with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment."

Unlike KRAS testing, EGFR testing of colorectal tumor cells has not demonstrated predictive value in determining the likelihood of a response to either cetuximab or panitumumab. Thus, this testing is not required to establish medical necessity or used in treatment determinations.

Head and Neck Carcinoma
In a phase three randomized, multicenter, placebo-controlled trial (Burtness, 2005) 117 individuals with metastatic squamous cell carcinoma of the head and neck (SCCHN) were assigned to receive either cisplatin with cetuximab (n= 57) or cisplatin plus placebo (n=60) as first-line therapy. The study allowed for substitution of carboplatin for cisplatin for individuals with worsening creatinine clearance or grade 2 neurotoxicity. The median followup time was 31 months. Thirteen individuals from the placebo arm with progressive disease crossed over to receive cetuximab. There was a statistically significant difference in the objective response rate (OR) of 10% OR for the control group and 26% OR for individuals receiving cisplatin with cetuximab (p=0.03). However, progression-free survival (PFS) was not statistically different between the treatment groups (p=.09). Median PFS was 2.7 months for the control group, and 4.2 months for the treatment group. Overall survival (OS) was also not statistically significant with 7.9 months in the control and 9.2 months in the treatment cohorts (p=0.21).

Vermorken and colleagues (2008) reported results from a phase three trial of 442 individuals with untreated recurrent or metastatic squamous cell carcinoma of the head and neck randomized to receive either cisplatin or carboplatin with fluorouracil, or the same chemotherapy regimen plus cetuximab. Participants with stable disease who received cetuximab on the treatment arm were allowed to continue receiving single agent cetuximab until disease progression or toxic effects. The median PFS was 3.3 months and 5.6 months for the control and cetuximab treatment cohorts, respectively (p < 0.001). Median OS was 7.4 months in the control group and 10.1 months in the treatment arm. There were nine cases of sepsis in the treatment group versus one case in the control group (p=0.02). The authors concluded, "the combination of platinum, fluorouracil and cetuximab significantly improved survival as compared with platinum and fluorouracil alone."

Since expression of EGFR has been detected in nearly all individuals with head and neck cancer, individuals enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR expression prior to study entry (Product Information Label, 2009).

Additional recommended off-label uses for cetuximab include single-agent, combination with chemotherapy, with or without radiation therapy for the treatment of recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck (American Hospital Formulary Service^® [AHFS^®], 2010; NCCN, 2009).

Non-Small Cell Lung Cancer (NSCLC)
Belani and colleagues (2008) reported results of 80 individuals in a multicenter phase two study of cetuximab in combination with carboplatin and docetaxel for individuals with advanced stage (stage IIIB with effusion, or stage IV) non-small cell lung cancer. Individuals were treated with cetuximab plus docetaxel and carboplatin every 21 days for up to 6 cycles. In individuals without evidence of disease progression continued on single-agent cetuximab for a maximum of 1 year or until disease progression. Twenty-five individuals received single-agent cetuximab as maintenance therapy for a median duration of 12 weeks. Treatment was discontinued due to disease progression in 50 patients, and resulting from adverse events in 16 patients. Overall response rate (OR) was 15% (1 individual with CR and 11 individuals with PR). Stable disease was noted in 18 (23%) individuals with 5 (28%) disease stabilization lasting > six months. Progressive disease was noted in 35 (44%) individuals. 1-year and 2-year survival rates were 36% and 16%, respectively. The authors concluded this novel combination of cetuximab with docetaxel and carboplatin demonstrated "modest activity" in individuals with previously untreated advanced or metastatic NSCLC.

A phase two study of 131 individuals with recurrent or metastatic NSCLC randomized participants to receive first-line therapy with either cisplatin or carboplatin with gemcitabine versus the same chemotherapy regimen with the addition of cetuximab (Butts, 2007). 18 individuals in the treatment arm (n=65) had a partial response compared to 12 individuals in the control arm (n=66). There was no statistically significant difference in the median PFS of 5.09 months versus 4.21 months for the treatment and control groups, respectively. There were no complete responses (CR) noted in the study. Partial responses (PR) were observed in 18 of 65 individuals in the treatment arm and in 12 of 66 individuals in the control arm. The authors concluded the addition of cetuximab may improve clinical outcomes, and larger studies are ongoing.

In a phase II randomized trial, 86 individuals were assigned to receive either cisplatin and vinorelbine, or the combination chemotherapy with cetuximab as first-line therapy. The authors noted the "most important exclusion criteria were proven or symptomatic brain metastasis, prior treatment with monoclonal antibodies or other EGFR-targeting treatments." The addition of cetuximab improved 1- and 2- year survival rates 33% (19-47) and 16% (5-27) compared to the chemotherapy alone arm with 26% (13-40) and 0%. Median PFS time favored the cetuximab cohort with 5 months versus 4.6 months for cisplatin and vinorelbine alone. Grade 3 and 4 asthenia and skin toxicities were more frequent in the cohort that received the combination chemotherapy with cetuximab. Results from an ongoing phase III, randomized trial are anticipated to validate the findings from the phase II trial (Rosell, 2008).

Additional recommended off-label uses for cetuximab include first-line therapy for stage IIIB and stage IV NSCLC with additional criteria (AHFS, 2010 and the NCCN, 2010).

Other Cancers
Casino and colleagues (2008) reported results from a phase II randomized trial of 84 individuals with advanced pancreatic carcinoma. 42 individuals were randomized to receive 1000mg/m² gemcitabine and 35 mg/m² cisplatin with cetuximab 250 mg/m² after the usual loading dose of 400 mg/m². The other 42 individuals were randomized to the same chemotherapy regimen without cetuximab. Objective response was the primary endpoint of the study. At a median follow-up of 11.8 months, there was no significant difference for objective response or disease control. Median progression-free survival was not significantly different between the cohorts, 3.4 months and 4.2 months for the cetuximab group and non-cetuximab group, respectively. Overall survival was not significantly different at 7.5 months for the cetuximab and 7.8 months for the non-cetuximab group. The investigators interpreted the addition of cetuximab did not have a significantly positive effect and therefore, "should not be further assessed in phase III trials."

Combination with another Monoclonal Antibody
In a phase 3, open-label trial, 755 individuals with metastatic, unresectable colon or rectal carcinoma were randomized to receive treatment with capecitabine-bevacizumab (CB) and oxaliplatin, or capecitabine-bevacizumab-cetuximab (CBC) with oxaliplatin. Seven hundred thirty-two individuals initiated treatment, with an equal distribution of 366 individuals in each group. The CBC cohort had a significantly decreased median progression-free survival (PFS) of 9.4 months compared to the CB group of 10.7 months, P=0.01. Overall quality of life and global health status in 532 individuals (276 in the CB group, 256 in the CBC group) improved significantly more in the CB group (P=0.007) compared to the CBC cohort (P=0.03). The investigators (Tol, 2009) concluded the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab "resulted in a significant decrease in progression-free survival and a poorer quality of life." Tol and colleagues noted the results from the combination of anti-VEGF and anti-EGFR antibodies in the phase 3 trial were unexpected and differed from results in earlier phase II studies such as the BOND-2 (Saltz, 2007) trial.

There are ongoing trials studying the expanded use of cetuximab for additional indications such as solid tumors including ovarian, esophageal and pancreatic cancers, and at different stages of various diseases (e.g., first-line of treatment for metastatic colorectal cancer). The use of cetuximab in combination with a variety of chemotherapy or other biologic agents is also under investigation.

Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum. The term colorectal cancer does not include anal cancer. Anal cancer refers to malignancies developing from anal tissue (e.g., anus, anal canal or anorectum) which include the opening of the rectum to the outer body. Anal cancer occurs infrequently and represents 4% of all cancers of the lower gastrointestinal tract (National Cancer Institute [NCI], 2009; NCCN, 2010).

According to the National Institutes of Health, (NCI, 2008), head and neck carcinomas account for approximately 6 percent of all cancers in the United States and are more common in men and in people over age fifty. Head and neck cancer includes cancers of the tongue, mouth, salivary glands, pharynx, larynx, sinus, and other sites located in the head and neck area.

About 90 percent of head and neck cancers are of the squamous cell variety and almost 100 percent of these express EGFR, which is critical for tumor growth. Therefore, as noted in the cetuximab product information (2009), and based on the entry criteria for individuals enrolled in the head and neck cancer clinical trials, pretreatment assessment for evidence of EGFR expression was not required for individuals with squamous cell carcinoma of the head and neck.

A monoclonal antibody is a protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells. Cetuximab is a monoclonal antibody that binds specifically to the human Epidermal Growth Factor Receptor. As a result, Cetuximab may interrupt the signals necessary for the cancer cells' growth and survival.

Adverse Events and Warnings:
Cetuximab carries a black box warning regarding severe infusion reactions that occurred in approximately 3% of individuals in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue infusion for serious infusion reactions. Serious reactions included rapid onset of airway obstruction (e.g., bronchospasm, stridor, hoarseness), hypotension, loss of consciousness and/or cardiac arrest. Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Those having severe infusion reactions with cetuximab should have their infusion stopped immediately and should not be re-treated with cetuximab. Individuals should be monitored for 1 hour following cetuximab infusion in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen) (Product Information, 2009).

Another black box warning of cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 individuals receiving cetuximab in combination with radiation therapy for SCCHN. These events did not occur in the control group of 212 individuals with SCCHN randomized to radiation therapy alone. Carefully consider use of cetuximab with radiation therapy in individuals with head and neck cancer with a history of coronary artery disease, congestive heart failure, and arrhythmias. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after cetuximab therapy (Product Information, 2009).

Pulmonary toxicity as evidenced by interstitial lung disease (ILD) has been reported in individuals with squamous cell carcinoma of the head and neck treated with cetuximab. However it is difficult to determine if cetuximab caused ILD since there are many other factors involved.

Cetuximab dermatologic toxicity can include skin reactions such as an acne-like rash, drying, cracking, inflammation, and infections (e.g., blepharitis, cellulitis, and cyst). These reactions may be worsened by sun exposure. In the event of a severe infusion reaction, the use of another monoclonal antibody or antineoplastic agent may be considered.

Adenocarcinoma: cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties

Anal cancer: cancer originating in the tissues of the anus; the anus is the opening of the rectum (last part of the large intestine) to the outside of the body

Apoptosis: a series of molecular steps resulting in a type of cell death; the body's normal way of getting rid of unneeded or abnormal cells; programmed cell death

Colon cancer: cancer originating in the tissues of the colon (the longest part of the large intestine); most colon cancers are adenocarcinomas that begin in cells that make and release mucus and other fluids

Colorectal cancer: cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus)

First-line of therapy: the first or primary treatment for the diagnosis; may include surgery, chemotherapy, radiation therapy or a combination of these therapies

Head and Neck Cancer: cancer that arises in the head or neck region (in the nasal cavity, sinuses, lips, mouth, salivary glands, throat, or larynx [voice box])

Metastasis: the spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread

Monoclonal antibody: a protein developed in the laboratory that can locate and bind to a specific substance in the body

Off-label: utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved labeling

Partial response: a decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission

Rectal cancer: cancer originating in tissues of the rectum (the last several inches of the large intestine closest to the anus)

Second-line therapy: treatment given when initial treatment (first-line therapy) is not effective or there is disease progression

Third-line therapy: treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression

Vascular endothelial growth factor (VEGF): a substance made by cells that stimulates new blood vessel formation

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Belani CP, Schreeder MT, Steis RG, et al. Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study. Cancer. 2008; 112(9): 2512-2517.
2. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol. 2008; 26(May 20 suppl; abstr 4000).
3. Bonner J, Harari P, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med. 2006; 354: 567–578.
4. Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 2005; 23(34):8646-8654.
5. Butts C, Bodkin D, Middleman E, et al. Randomized phase II study of gemcitabine plus cisplatin, with or without cetuximab, as first-line therapy for patients with advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2007; 25(36): 5777-5782.
6. Cascinu S, Berardi R, Labianca R, et al.; Italian Group for the Study of Digestive Tract Cancer (GISCAD). Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008; 9(1):39-44.
7. Cervantes A, Macarulla T, Martinelli E, et al. Correlation of KRAS status (wild type [wt] vs. mutant [mt]) with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2008; 26(May 20 suppl; abstr 4129).
8. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004; 351:337-345.
9. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008; 508-515.
10. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007; 357(20):2040-2048.
11. Karpetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359(17):1757-1765.
12. Lenz HJ, Cutsem EV, Khambata-Ford S, et al. Multicenter phase II translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. J Clin Onc. 2006; 24(30): 4914-4921.
13. Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008; 359(17): 1834-1836.
14. Rosell R, Robinet G, Szczesna A, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as fist-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol. 2008; 19: 362-369.
15. Saltz LB, Lenz HJ, Kindler L, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007; 25(29): 4557-4561.
16. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009; 360(6): 563-572.
17. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360: 1408-1417
18. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 359(11): 1116-1127.
19. Xiong HQ, Rosenberg A, LoBuglio A, et al: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2004; 22(13):2610-2616.
20. Zhu Z. Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor: status and perspectives. Acta Pharmacol Sin. 2007; 28(9):1476-1493.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009.
2. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2010^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2010.
3. Cetuximab (systemic). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated February 5, 2010. Available at: http://www.thomsonhc.com. Accessed on March 3, 2010.
4. Erbitux (cetuximab) [Product Information]. Branchburg, NJ. ImClone Systems Incorporated. July 22, 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125084s167lbl.pdf. Accessed on March 3, 2010.
5. National Cancer Institute (NCI) – Colon cancer treatment (PDQ^®). Last modified November 10, 2009. Available at: http://www.nci.nih.gov/cancertopics/types/colon-and-rectal. Accessed on March 3, 2010.
6. National Cancer Institute (NCI) - Head and Neck Cancer: Questions and Answers. March 9, 2005. Available at: http://www.cancer.gov/cancertopics/factsheet/Sites-Types/head-and-neck. Accessed on March 3, 2010.
7. National Cancer Institute (NCI) –Rectal cancer treatment (PDQ). Last modified December 12, 2008. Available at: http://www.nci.nih.gov/cancertopics/pdq/treatment/rectal/healthprofessional. Accessed on March 3, 2010.
8. NCCN Clinical Practice Guidelines in Oncology™. © 2009. National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org/index.asp. Accessed on March 3, 2010.
   • Anal Carcinoma (V.1.2010). Revised October 20, 2009.
   • Colon Cancer (V.2.2010). Revised February 8, 2010.
   • Head and Neck Cancers (V.1.2009). Revised May 27, 2009.
   • Non-small Cell Lung Cancer (V.2.2010). Revised March 5, 2010.
   • Rectal Cancer (V.2.2010). Revised February 8, 2010.
     

1. American Cancer Society. Available at: http://www.cancer.org/docroot/home/index.asp.  Accessed on March 3, 2010.
2. National Cancer Institute. Dictionary of Cancer Terms. Available at: http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46066. Accessed on March 3, 2010.

Cetuximab
Epidermal Growth Factor Receptor (EGFR)
Erbitux
Monoclonal Antibody
Vectibix

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.