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Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) frequently overexpressed and activated in non-small cell lung cancer (NSCLC). Mutations in two regions of the EGFR gene (exons 18-24) --small deletions in exon 19 and a point mutation in exon 21 (L858R) -- appear to predict tumor response to tyrosine kinase inhibitors (TKIs) such as erlotinib. This policy summarizes the evidence for using EGFR mutations to decide which patients with advanced NSCLC should be considered for erlotinib therapy and which are better suited for alternative therapies.
Treatment options for NSCLC depend on disease stage and include various combinations of surgery, radiation therapy, chemotherapy, and best supportive care. Unfortunately, in up to 85% of cases, the cancer has spread locally beyond the lungs at diagnosis, precluding surgical eradication. In addition, up to 40% of patients with NSCLC present with metastatic disease. When treated with standard platinum-based chemotherapy, patients with advanced NSCLC have a median survival of 8 to 11 months and a 1-year survival of 30% to 45%.
Laboratory and animal experiments have shown that therapeutic blockade of the EGFR pathway could be used to halt tumor growth in solid tumors that express EGFR. These observations led to the development of 2 main classes of anti-EGFR agents for use in various types of cancer: small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies that block EGFR-ligand interaction.
Three orally administered EGFR-selective small molecule TKIs have been identified for use in treating NSCLC: gefitinib (Iressa®, AstraZeneca), erlotinib (Tarceva®, OSI Pharmaceuticals), and afatinib (Gilotrif™, Boehringer Ingelheim). Only erlotinib and afatinib are approved by the U.S. Food and Drug Administration (FDA); gefitinib may be continued in patients already receiving gefitinib in the U.S.
Erlotinib received initial FDA approval in 2004 for second-line treatment of patients with advanced NSCLC. In 2013, erlotinib indications were expanded to include first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. A companion diagnostic test, the cobas® EGFR Mutation Test, was coapproved for this indication. Afatinib was FDA-approved in July 2013 for first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletions or L858R mutations. A companion diagnostic test, the therascreen® EGFR Rotor-Gene Q polymerase chain reaction (RGQ PCR) kit, was coapproved for this indication.
Both tests are polymerase chain reaction (PCR) assays. FDA-approved product labels for both erlotinib and afatinib indicate that EGFR mutations must be “detected by an FDA-approved test” but do not specify which test must be used.
POLICYExcept as noted below, analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to erlotinib or afatinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded (see Policy Guidelines sections).
Analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) -- is considered investigational for patients with advanced NSCLC of squamous cell-type.
Analysis for other mutations within exons 18-24, or other applications related to NSCLC, is considered investigational.
The test is intended for use in patients with advanced NSCLC. Patients with either small deletions in exon 19 or a point mutation in exon 21 (L858R) of the tyrosine kinase domain of the epidermal growth factor gene are considered good candidates for treatment with erlotinib or afatinib. Patients found to be wild type are unlikely to respond to erlotinib or afatinib; other treatment options should be considered.
Current (2014) guidelines from the National Comprehensive Cancer Network recommend EGFR mutation testing:
Current (2014) guidelines issued jointly by the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology recommend:
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY7/27/2006: Approved by Medical Policy Advisory Committee (MPAC)
8/16/2007: Policy reviewed, no changes
1/06/2009: Policy reviewed. No changes.
04/25/2011: Policy description updated. Policy statement revised to state that analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to erlotinib in patients with advanced NSCLC. Other applications related to NSCLC remain investigational. Code Reference section changed from non-covered to covered.
02/24/2012: Policy reviewed; no changes.
01/10/2013: Added the following new 2013 CPT code to the Code Reference section: 81235. Added ICD-9 codes 162.3 - 162.9 to the Code Reference section.
09/16/2014: Policy title changed from "Epidermal Growth Factor Receptor for Patients with Non-Small Cell Lung Cancer (NSCLC)" to "Epidermal Growth Factor Receptor Mutation Analysis for Patients with Non-Small-Cell Lung Cancer." Policy description revised. Medically necessary policy statement revised to state: Except as noted below, analysis of two types of somatic mutation within the EGFR gene – small deletions in exon 19 and a point mutation in exon 21 (L858R) – may be considered medically necessary to predict treatment response to erlotinib or afatinib in patients with advanced lung adenocarcinoma or in whom an adenocarcinoma component cannot be excluded. Policy guidelines updated regarding EGFR mutation testing.
SOURCE(S)Blue Cross Blue Shield Association Policy # 2.04.45
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.