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DESCRIPTIONThe epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (TK), is frequently overexpressed and activated in non-small cell lung cancer (NSCLC). Two EGFR tyrosine kinase inhibitor (TKI) drugs, erlotinib and gefitinib, block intracellular receptor phosphorylation, dampening signal transduction through pathways downstream to the EGF receptor, such as the RAS/RAF/MAPK cascade. RAS proteins are G-proteins that cycle between active and inactive 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 important in cancer cell proliferation, invasion, metastasis and stimulation of neovascularization.
The KRAS gene (which encodes for the RAS proteins) can harbor oncogenic mutations that result in a constitutively activated protein, independent of signaling from the EGF receptor, possibly rendering a tumor resistant to therapies that target the EGF receptor (e.g., TKIs). KRAS mutations are found in approximately 15–30% of lung adenocarcinomas.
Erlotinib (Tarceva®) received approval from the U.S. Food and Drug Administration (FDA) in November 2004 as salvage therapy for advanced NSCLC, based on results of a phase III clinical trial that demonstrated a modest survival benefit, 6.7 months median survival compared to 4.7 months in the placebo group. Gefitinib (Iressa®) was approved by the FDA in 2003 through the agency’s accelerated approval process, based on the initially promising results of phase II trials. The labeled indication was limited to patients with NSCLC who had failed 2 or more prior chemotherapy regimens. However, in December 2004, results of phase III trials became available, suggesting that gefitinib was not associated with a survival benefit. In May 2005, the FDA revised the labeling of gefitinib to further limit its use to patients who were currently benefiting from the drug, or who had benefited in the past, and that no new patients were to be given the drug.
Although gefitinib fell out of use in the U.S. in 2005, it continued to be used elsewhere in the world and a recent study was published ("Iressa in NSCLC Trial Evaluating Response and Survival vs Taxotere," or "INTEREST" trial) that involved 1,466 patients from 24 countries outside of the U.S. (1) All of the patients had advanced or metastatic disease and had been previously treated with at least 1 platinum-containing regimen, and were randomized to receive either gefitinib or docetaxel. Of the 1,466 patients, 1433 were evaluable. Objective tumor response rates, progression-free and overall survival were similar for the 2 groups; however, gefitinib was associated with lower rates of treatment-related adverse events than docetaxel. The authors state that based on their findings, they are hopeful that gefitinib can return as a treatment for lung cancer in the U.S.
Because gefitinib is currently in very limited use in the U.S. and only as part of a special access program, this policy will only address studies that assess the response to erlotinib in relation to the presence or absence of KRAS mutations in NSCLC. KRAS mutation analysis is commercially available to test NSCLC from Genzyme Genetics and Medical Solutions™.
Several studies have reported that somatic mutations in the EGFR gene TK ATP-binding domain predict sensitivity to these targeted therapies.
Anti-EGFR monoclonal antibodies
Anti-EGFR monoclonal antibodies include cetuximab and panitumumab. Recent conclusive evidence has shown that patients with metastatic colorectal cancer whose tumors harbor KRAS mutations do not respond to EGFR monoclonal antibodies, as summarized in a TEC Assessment. Cetuximab is used in combination with chemotherapy in patients with advanced or recurrent NSCLC as first-line and maintenance therapy.
KRAS mutation analysis is commercially available to test NSCLC, and laboratories performing the test include Genzyme Genetics and Medical Solutions™.
Several studies have shown that EGFR and KRAS mutations are mutually exclusive. Although several of the studies outlined in this policy that analyzed KRAS mutations also tested for other markers in NSCLC (e.g., EGFR mutations), only the data from each study as they relate to KRAS are presented in the policy.
POLICYAnalysis of somatic mutations of the KRAS gene is considered investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitor erlotinib and the anti-EGFR monoclonal antibody cetuximab in non-small cell lung carcinoma.
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.
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 HISTORY3/2/2009: Policy added
04/23/2010: Policy description and statement unchanged. FEP verbiage added to the Policy Exceptions section.
04/25/2011: Added information regarding anti-EGFR monoclonal antibodies to the policy description. Policy statement revised to state that analysis of somatic mutations of the KRAS gene is considered investigational as a technique to predict treatment non-response to anti-EGFR therapy with the tyrosine-kinase inhibitor erlotinib and the anti-EGFR monoclonal antibody cetuximab in non-small cell lung carcinoma.
02/24/2012: Policy reviewed; no changes.
01/01/2013: Added CPT codes 81275 and 81403 to the Code Reference section.
03/13/2014: Policy reviewed; no changes to policy statement. Removed deleted CPT codes 83890-83914 from the Code Reference section.
12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81403.
07/31/2015: Code Reference section updated for ICD-10.
12/31/2015: Investigative definition updated in policy guidelines section. Code Reference section updated to revise code description for CPT code 81275 with an effective date of 01/01/2016.
01/26/2016: Code Reference section updated to add new 2016 CPT code 81276.
06/09/2016: Policy number added.
SOURCESBlue Cross Blue Shield Association policy # 2.04.55
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.