Medical Policy: 02.04.55
Original Effective Date: June 2016
Reviewed: May 2019
Revised: May 2019
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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.
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.
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.
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.
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 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:
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.
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:
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