Medical Policy: 02.04.55 

Original Effective Date: June 2016 

Reviewed: May 2019 

Revised: May 2019 



This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.



EGFR is a growth factor receptor that is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately leading to cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many solid tumors. Targeted therapies directed to tumors harboring activating mutations within the EGFR tyrosine kinase domain (exons 18-21) have demonstrated some success in treating a subset of patients with non-small-cell lung cancer (NSCLC) by preventing ATP-binding at the active site. Gefitinib and erlotinib have been approved by the FDA for use in treating patients with NSCLC who previously failed to respond to the traditional platinum-based doublet chemotherapy. These 2 drugs have also recently been shown to increase progression-free and overall survival in patients who receive EGFR-tyrosine kinase inhibitor therapy as a first-line therapy for the treatment of NSCLC. Approval for osimertinib (Tagrisso™) is for patients who have progressed on or after EGFR tyrosine kinase inhibitor therapy. Analysis of the T790M variants in the EGFR gene can predict the response to osimertinib (Tagrisso™).


Agents such as gefitinib and erlotinib, which prevent ATP binding to EGFR kinase, do not appear to have any meaningful inhibitor activity on tumors that demonstrate the presence of the specific drug-resistant EGFR mutation T790M. Therefore, current data suggest that the efficacy of EGFR-targeted therapies in NSCLC is confined to patients with tumors demonstrating the presence of EGFR- activating mutations such as L858R, L861Q, G719A/S/C, S768I or small deletions within exon 19 and the absence of the drug-resistant mutation T790M. As a result, the variation status of EGFR can be a useful marker by which patients are selected for EGFR-targeted therapy.


Gene Amplification

Another issue related to EGFR and NSCLC is gene amplification, which is defined as the presence of an increased number of copies of a specific gene fragment in a chromosome. This is measured using a laboratory method referred to as in-situ hybridization. Gene amplification may lead to production of increased numbers of a gene copies, a process referred to as elevated gene expression. Gene expression is measured by immunohistochemical testing.


It has been proposed that the measurement of EGFR amplification in NSCLC tumor tissue can be used for the prediction of response to TKI drug therapy. The evidence regarding this question is currently mixed.


The use of EGFR amplification testing for conditions other than NCSLC has been limited. There have been several small studies that have investigated the use of EGFR amplification status in subjects with glioblastoma, head and neck squamous cell cancer (HNSCC), colon and gastric cancers. Several of these studies have shown some benefit from EGFR amplification testing. However, at this time the clinical utility of such testing has not been established.


Both EGFR mutation analysis (PCR amplification and gene sequencing) and EGFR gene amplification (fluorescence in-situ hybridization or FISH) are commercially available (Genzyme Genetics Westborough, MA). These tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Pre-market approval from the FDA is not required when the assay is performed in a laboratory that observes the CLIA regulations.


Proteomic Testing

The term proteome refers to the entire complement of proteins produced by an organism or cellular system, which may vary over time and in response to selected stressors, and proteomics refers to the large-scale comprehensive study of a specific proteome. A cancer cell’s proteome is related to its genome and to genomic alterations, but may not be static over time. The proteome may be measured with mass spectrometry (MS) or protein microarray. For cancer, proteomic signatures in the tumor or in bodily fluids (ie, pleural fluid or blood) other than the tumor have been investigated as a biomarker for cancer activity.


Proteomic testing has been proposed as a way to predict survival outcomes and the response to and selection of targeted therapy for patients with non-small-cell lung cancer (NSCLC). One commercially available test, the VeriStrat® assay, has been investigated as a predictive marker for response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).


For individuals with newly diagnosed NSCLC and unknown EGFR variant status who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes 4 retrospective studies and a prospective study. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. All study populations were either unselected for EGFR-variant status or status was expressly reported as unknown in conjunction with negative or positive status reports. None of the studies that reported unknown EGFR-variant status reported outcomes for the proteomic score based on unknown EGFR-variant status. The evidence is insufficient to determine the effects of the technology on health outcomes.


NCCN Guidelines

The NCCN guideline for the treatment of NSCLC (Version 4.2019) recommends routine testing for epidermal growth factor receptor (EGFR) variants in patients with metastatic nonsquamous NSCLC (category 1 recommendation) and consideration for EGFR-variant testing in patients with metastatic squamous NSCLC who were never smokers or with small biopsy specimens or mixed histology (category 2A recommendation). Recommendations for first-line treatment for EGFR-positive patients with advanced or metastatic NSCLC, and EGFR-negative or -unknown patients as well as for patients in either category who have progressed on therapy are provided.


As use of NGS testing increases, additional EGFR variants are increasingly identified: however the clinical implications of individual alterations are unlikely to be well established in patients with squamous cell carcinoma, the frequency of EGFR mutations does not justify routine testing of all tumor specimens.


American Society of Clinical Oncology

The American Society of Clinical Oncology (2017) updated its clinical practice guidelines on systemic therapy for stage IV NSCLC.New or revised recommendations included the following recommendations: first-line treatment for patients with nonsquamous cell carcinoma or squamous cell carcinoma (without positive markers, eg, EGFR, ALK, ROS1), based on programmed death-ligand 1 expression; second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy based on programmed death-ligand 1 expression; as well as recommendations for those patients who cannot receive immune checkpoint inhibitor. Recommendations are included for patients with a sensitizing EGFR variant, for patients with disease progression after first-line EGFR tyrosine kinase inhibitor therapy based on the results of T790M variant testing, and for patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib, or if they previously received crizotinib, they may be offered chemotherapy.


The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology released a joint guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors (2018). This document has a strong recommendation stating, "In lung adenocarcinoma patients who harbor sensitizing EGFR mutations and have progressed after treatment with an EGFR-targeted tyrosine kinase inhibitor, physicians must use EGFR T790M mutational testing when selecting patients for third-generation EGFR-targeted therapy." Regarding circulating tumor cell testing, they state the following:

  • There is currently insufficient evidence to support the use of circulating plasma cfDNA molecular methods for establishing a primary diagnosis of lung adenocarcinoma (no recommendation; insufficient evidence, confidence, or agreement to provide a recommendation).
  • In some clinical settings in which tissue is limited and/or insufficient for molecular testing, physicians may use a cfDNA assay to identify EGFR mutations (recommendation; some limitations in quality of evidence).
  • Physicians may use plasma cfDNA methods to identify EGFR T790M mutations in lung adenocarcinoma patients with progression or secondary clinical resistance to EGFR-targeted TKIs; testing of the tumor sample is recommended if the plasma result is negative (expert consensus opinion; serious limitations in quality of evidence).


Although the ability to obtain genomic information has expanded with the advent of next generation sequencing (NGS), the capacity to synthesize and apply this information is still quite limited. The intended place for plasma based testing in therapy woulb be as an alternative to tissue EGFR testing, but at this time the lower sensitivity of plasma testing compared with tissue testing and the high rate of false negatives of plasma testing and overall limitations in quality of evidence make plasma testing for EGFR mutation status currently investigational.


Prior Approval:

Not applicable



For additional testing please see policy 02.04.63 Expanded Genetic Panels to Identify Targeted Cancer Therapy and 02.04.16 Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsies)


Analysis of variants in the gene (only at exons 19 and 21) for the epidermal growth factor receptor (EGFR) is considered medically necessary as a technique to predict treatment response for individuals with non-small cell, non-squamous cell lung cancer undergoing treatment with EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®], osimertinib [Tagrisso], dacomitinib [Vizimpro], gefitinib [Iressa®], or afatinib [Gilotrif®]).


Analysis of variants in the gene (only at exons 19and 21) for the epidermal growth factor receptor (EGFR) is considered medically necessary as a technique to predict treatment response for individuals with squamous cell lung cancer and large cell carcinoma ;undergoing treatment with EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva®], osimertinib [Tagrisso], dacomitinib [Vizimpro], gefitinib [Iressa®], or afatinib [Gilotrif®]).


Analysis for the T790M variants in the gene for the EGFR is considered medical necessary as a technique to predict treatment response in those who have progressed on or after EGFR TKI therapy.


The use of proteomic testing, including but not limited to the VeriStrat assay, is considered investigational.


Analysis of mutations in the gene for epidermal growth factor receptor (EGFR) is considered investigational for all other indications, including squamous cell-type and colon cancer.


Analysis of gene amplification for epidermal growth factor receptor (EGFR) is considered investigational, including as a technique to predict treatment response to tyrosine kinase inhibitor therapy (for example, erlotinib [Tarceva®], gefitinib [Iressa®], or afatinib [Gilotrif®]) in individuals with non-small cell lung cancer (NSCLC).


The following analyses/tests are considered investigational:

  • Testing for EGFR or variants for purposes other than for treatment selection or
  • Analysis of other EGFR sensitizing variants within exons 18 to 24 for applications related to NSCLC
  • Expanded panel testing to determine EGFR status


Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 0022U Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence/absence of variants and associated therapy(ies) to consider
  • 81235 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)
  • 81401 Molecular pathology procedure, Level 2
  • 81479 Unlisted molecular pathology procedure
  • 81538 Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival (i.e. VeriStrat).
  • 88365 In situ hybridization (eg, FISH), per specimen; initial single probe stain procedure


Selected References:

  • Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol. 2009; 27(36):6251-6266.
  • Blue Cross Blue Shield Association. Epidermal growth factor receptor mutations and tyrosine kinase inhibitor therapy in advanced non-small-cell lung cancer. TEC Assessment, 2007; 22(6).
  • Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy J Clin Oncol. 2011; 29(15):2121-2127.
  • Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn. 2013; 15(4):415-453
  • van Zandwijk N, Mathy A, Boerrigter L, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18(1):99-103.
  • da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010; 116(24):5599-5607.
  • Douillard JY, Pirker R, O'Byrne KJ, et al. Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2014; 9(5):717-724.
  • Rosell R, Moran T, Queralt C, et al.; Spanish Lung Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009; 361(10):958-967.
  • National Comprehensive Cancer Network. (2016). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-Small Cell Lung Cancer. Version 4.2019.
  • Leighl, Natasha B. et al. “Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline.” Journal of Clinical Oncology 32.32 (2014): 3673–3679.
  • Hanna N, Johnson D, Temin S, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. Oct 20 2017;35(30):3484-3515. PMID 28806116
  • American Society of Clinical Oncology (ASCO). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. 2017. doi/pdf/10.1200/JCO.2016.71.9807
  • Akerley WL, Arnaud AM, Reddy B, et al. Impact of a multivariate serum-based proteomic test on physician treatment recommendations for advanced non-small-cell lung cancer. Curr Med Res Opin. Jun 2017;33(6):1091-1097. PMID 28277859
  • Grossi F, Genova C, Rijavec E, et al. Prognostic role of the VeriStrat test in first line patients with non-small cell lung cancer treated with platinum-based chemotherapy. Lung Cancer. Mar 2018;117:64-69. PMID 29395121
  • Qin A, Ramnath N. The "liquid biopsy" in non-small cell lung cancer - not quite ready for prime time use. Transl Cancer Res. 2016;5(Suppl 4):S632–S635. doi:10.21037/tcr.2016.10.29
  • National Institute for Helath and Care Excellence NICE Guideance. Plasma EGFR mutation tests for adults with locally advanced or metastatic non-small-cell-lung cancer. 18 January 2018.
  • Clinical Tracking non-small cell lung cancer evolution through therapy (Rx) (TRACERx).


Policy History:

  • May 2019 - Annual Review, Policy Revised
  • May 2018 - Annual Review, Policy Revised
  • May 2017 - Annual Review, Policy Revised
  • June 2016 - New Policy, Policy Implemented

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.


*CPT® is a registered trademark of the American Medical Association.