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DESCRIPTIONCetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.
The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. RAS proteins are G-proteins that cycle between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. KRAS mutations are found in approximately 30–50% of CRC tumors and are common in other tumor types. Another proto-oncogene that acts downstream from KRAS–NRAS harbors oncogenic mutations in codons 12, 13, or 61 that result in constitutive activation of the EGFR-mediated pathway. These mutations are relatively rare compared with KRAS, detected in perhaps 2% to 7% of CRC specimens. It is unclear whether NRAS mutations predict poor response to anti-EGFR monoclonal antibody therapy or are prognostic of poor CRC outcome in general. A third proto-oncogene, BRAF, encodes a protein kinase and is involved in intracellular signaling and cell growth and is a principal downstream effector of KRAS. BRAF mutations occur in less than 10–15% of colorectal cancers, and appear to be a marker of poor prognosis. KRAS and BRAF mutations are considered to be mutually exclusive.
Cetuximab and panitumumab have FDA marketing approval for treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy.
KRAS, NRAS, and BRAF mutation analyses using PCR methodology are commercially available as laboratory-developed tests. Such tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.
This policy summarizes the evidence for using tumor cell KRAS, NRAS, and BRAF mutational status as a predictor of response to EGFR-targeted therapy with monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer.
KRAS mutation analysis may be considered medically necessary for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab and panitumumab.
NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.
BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY10/9/2008: Policy added
11/20/2008: Approved by Medical Policy Advisory Committee
12/28/2010: Policy title and description updated to indicate inclusion of BRAF testing to the policy; BRAF testing policy statement added as investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer; KRAS policy statement unchanged. FEP verbiage added to the Policy Exceptions section. Added HCPCS S3713 to the Covered Codes table.
01/18/2012: Policy reviewed; no changes.
01/10/2013: Added CPT codes 81210, 81403, and 81275 to the Code Reference section.
04/08/2014: Policy description updated. Kras policy statement updated with the following minor wording changes: “to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer” was changed to “for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.” Removed deleted HCPCS code S3713 from the Covered Codes table in the Code Reference section.
12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81403.
08/31/2015: Policy title changed from "KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer" to "KRAS, NRAS, and BRAF Mutation Analysis in Metastatic Colorectal Cancer." Policy description updated to include information regarding NRAS. Added the following policy statement: NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer. Added CPT code 81404 to the Investigational Codes table.
12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions. Code Reference section updated to revise code descriptions for CPT codes 81275 and 81210 with an effective date of 01/01/2016. Added new 2016 CPT code 81311 to the investigational codes table.
01/26/2016: Code Reference section updated to add new 2016 CPT code 81276.
06/06/2016: Policy number added.
SOURCE(S)Blue Cross & Blue Shield Association Policy # 2.04.53
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.