Cetuximab
DESCRIPTION
Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). EGFR is a transmembrane glycoprotein expressed in multiple normal epithelial tissues and in many human cancers. By binding to the EGFR, cetuximab competitively inhibits the binding of natural ligands, including epidermal growth factor (EGF). This blocks the complex downstream signaling of the EGFR cascade and results in inhibition of cell growth, induction of apoptosis and decreased production of matrix metalloproteinase and vascular endothelial growth factor (VEGF).
In the EGFR cascade, RAS proteins, including KRAS, normally function as switches in the kinase pathway activated between cell surface EGFR and downstream signaling. Mutations in the KRAS gene, occurring in 30% to 50% of colorectal cancers and common in other tumor types, activate the EGFR pathway and bypass the need for ligand binding. This renders cetuximab and other anti-EGFR agents ineffective against those tumors expressing KRAS mutations.
Another common mutation is found in the BRAF gene, a serine/threonine kinase. BRAF encodes a component downstream of the RAS proteins in the EGFR cascade. The BRAF gene is important for transducing mitogenic signals from the cell surface. BRAF mutations have been found in thyroid, colorectal and lung cancers as well as in a majority of malignant melanomas, however specific targeting and treatment of BRAF-dependent tumors remains under investigation.
An example of a preparation of cetuximab is Erbitux®.
REFER TO DECISION SUPPORT TREE
POLICY
Cetuximab for the treatment of colorectal carcinoma is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Cetuximab for the treatment of carcinoma of the head and neck is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Cetuximab for the treatment of non-small cell lung cancer is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Cetuximab for the treatment of other conditions/diseases is considered investigational.
Testing for mutation of the BRAF gene in the use of cetuximab is considered investigational.
MEDICAL APPROPRIATENESS
Cetuximab is considered medically appropriate for the treatment of ANY ONE of the following:
Colorectal carcinoma with ALL of the following:
Disease is metastatic
KRAS gene is normal (e.g., without mutation, wild type)
Treatment as ANY ONE of the following:
Single agent if individual has ANY ONE of the following:
Failure of ALL of the following:
Irinotecan-based regimen
Oxaliplatin-based regimen
Intolerance to irinotecan-based regimen
Combination agent with irinotecan-based regimen if the individual is refractory to irinotecan-based regimen
First-line therapy in combination with ANY ONE of the following regimens:
Oxaliplatin, fluorouracil and leucovorin (FOLFOX)
Irinotecan, fluorouracil and leucovorin (FOLFIRI)
Carcinoma of the head and neck with ALL of the following:
Disease is squamous cell carcinoma
Treatment as ANY ONE of the following:
A single agent with progression after platinum-based therapy for recurrent or metastatic disease
Combination therapy with radiation therapy for locally or regionally advanced disease
Combination therapy with platinum-based therapy for advanced disease
Non-small cell lung cancer with ALL of the following:
Disease is recurrent or metastatic
Treatment is in combination with vinorelbine and cisplatin
Individual is 18 years of age or older
Disease is stage IIIB (pleural effusion)or IV
Disease is EGFR expression positive
No known brain metastases exist
No prior chemotherapy or anti-EGFR therapy
APPLICABLE TENNESSEE STATE MANDATE REQUIREMENTS
Tennessee State law requires coverage of off-label indications of Food and Drug Administration (FDA) approved drugs when the off-label use is relative to life-threatening illnesses, such as cancer, AIDS, and coronary heart disease and recognized in one of the standard reference compendia (As defined in the statute: The United States Pharmacopoeia Drug Information, The American Medical Association Drug Evaluations, & The American Hospital Formulary Service Drug Information) or in the medical literature. This law is applicable to all fully insured members. The law is not applicable to self-funded accounts, but coverage for off-label uses may be provided based on the contractual agreement.
IMPORTANT REMINDER
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.
ADDITIONAL INFORMATION
For appropriate dosage information, contraindications, precautions, warnings, and monitoring information, please refer to one of the standard reference compendia (e.g., The American Hospital Formulary Service Drug Information).
KRAS mutation testing by polymerase-chain reaction (PCR) methods is performed by Clinical Laboratory Improvement Amendments licensed (CLIA-licensed) laboratories.
No controlled studies were found in the published literature that validate the administration of cetuximab for the treatment of other diseases/conditions.
SOURCES
BlueCross BlueShield Association. Medical Policy Reference Manual. (11:2010). KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer. (2.04.53). Retrieved January 6, 2011 from BlueWeb.
Bokemeyer, C., Bondarenko, I., Makhson, A., Hartmann, J. T., Aparicio, J., de Braud, F., et al., (2009). Fluorouracil, leucovorin and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. Journal of Clinical Oncology, 27 (5), 663-671. (Level 1 evidence - Industry sponsored).
Jimeno, A., Messersmith, W. A., Hirsch, F. R., Franklin, W. A., Eckhardt, S. G. (2009). KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: Practical application of patient selection. Journal of Clinical Oncology, 27 (7), 1130-1141.
Lexi-Comp Online. (2009). AHFS DI. Cetuximab. Retrieved January 29, 2009 from Lexi-Comp Online with AHFS.
Linardou, J., Dahabreh, I., Kanaloupiti, D., Siannis. F., Bafaloukos, Kosmidis, P., et al. (2008). Assessment of somatic KRAS mutations as a mechanism associated with resistance to EGFR-targeted agents: A systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncology, 9, 962-972.
MICROMEDEX Healthcare Series. Drugdex Drug Evaluations. (2009). Cetuximab. Retrieved January 27, 2009 from MICROMEDEX Healthcare Series.
National Comprehensive Cancer Network. (2008). NCCN Drugs & Biologics Compendium™. Cetuximab. Retrieved January 27, 2009 from http://www.nccn.org/professionals/drug_compendium/mainpage.aspx.
Pirker, R., Pereira, J. R., Szczesna, A., von Pawel, J., Krzawski, M., Ramlau, R., et al. (2009). Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open randomized phase III trial. The Lancet, 373 (9674), 1525-1531.
Technology Evaluation Center. (2009, January). KRAS mutation and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. (Vol. 23, No. 6) Retrieved February 3, 2009 from http://blueweb.bcbs.com/global_assets/special_content/tec_assessments/vol23/23_06.pdf. (29 articles and/or guidelines reviewed)
Tol, J., Koopman, M. Cats, A., Rodenburg, C. S. Creemmers, G. J., Schrama, J. G., et al. (2009). Chemotherapy, bevacizumab and cetuximab in metastatic colorectal cancer. The New England Journal of Medicine, 360 (6), 563572.
U. S. Food and Drug Administration. (2007, October). Center for Drug Evaluation and Research. Erbitux® (Cetuximab) label. Retrieved February 3, 2009 from http://www.fda.gov/cder/foi/label/2007/125084s103lbl.pdf.
U. S. Food and Drug Administration. (2008, September). Center for Drug Evaluation and Research. Erbitux® (Cetuximab) approval letter. Retrieved January 27, 2009 from http://www.fda.gov/cder/foi/appletter/2008/125084s139ltr.pdf.
ORIGINAL EFFECTIVE DATE: 3/10/2005
MOST RECENT REVIEW DATE: 2/23/2011
ID_BT
Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.
Pharmaceutical Decision Support Tree
Cetuximab (Erbitux®)
Does the individual have a request for BRAF mutation testing?
If yes, this does not meet medical necessity and/or medical appropriateness criteria
If no, go to question #2
Does the individual have a diagnosis of colorectal carcinoma with ALL the following?
Disease is metastatic
KRAS gene is normal (e.g., without mutation, wild type)
If yes, go to question #3
If no, go to question #4
Is the individual to receive treatment as ANY ONE of the following?
Single agent with failure of irinotecan-based regimen and oxaliplatin-based regimen or intolerance to irinotecan-based regimen
Combination agent with irinotecan-based regimen if the individual is refractory to irinotecan-based regimen
First-line therapy in combination with oxaliplatin, fluorouracil and leucovorin (FOLFOX) or irinotecan, fluorouracil and leucovorin (FOLFIRI)
If yes, this satisfies medical necessity and medical appropriateness criteria
If no, this does not meet medical necessity and/or medical appropriateness criteria
Does the individual have a diagnosis of squamous cell head and neck carcinoma and treatment is as ANY ONE of the following?
A single agent with progression after platinum-based therapy for recurrent or metastatic disease
Combination therapy with radiation therapy for locally or regionally advanced disease
Combination therapy with platinum-based therapy for advanced disease
If yes, this satisfies medical necessity and medical appropriateness criteria
If no, go to question #5
Does the individual have a diagnosis of non-small cell lung cancer and ALL the following?
Treatment is in combination with vinorelbine and cisplatin
Individual is 18 years of age or older
Disease is stage IIIB (pleural effusion)or IV
Disease is EGFR expression positive
No known brain metastases exist
No prior chemotherapy or anti-EGFR therapy
If yes, this satisfies medical necessity and medical appropriateness criteria
If no, this does not meet medical necessity and/or medical appropriateness criteria
This document has been classified as public information.