Medical Policy: 02.04.55 

Original Effective Date: June 2016 

Reviewed: May 2021 

Revised: May 2021 

 

Notice:

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.

 

Description:

This policy addresses Epidermal Growth Factor Receptor (EGFR) mutation analysis for all indications except non-small cell lung cancer (NSCLC). EGFR mutation analysis for non-small cell lung cancer (NSCLC) see medical policies: 02.04.78 Molecular Analysis for Targeted Therapy of Non-Small Cell Lung Cancer and 02.04.79 Circulating Tumor DNA for Management of Non-Small Cell Lung Cancer (Liquid Biopsy).  

 

Epidermal Growth Factor Receptor (EGFR) (also called HER1 gene or ERBB1 gene) is a gene that makes a protein that is involved in cell growth and cell survival. EGFR activating mutations are found in exons 18 to 21 of the EGFR gene, which is part of the gene coding for the tyrosine kinase domain of the EGFR protein. 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) (see medical policies referenced above). Because of its critical role in tumor aggressiveness, EGFR has been an attractive target for anticancer therapy in cancers other than non-small cell lung cancer (NSCLC).

 

The functional activation of EGFR via mutation or amplification/overexpression has been identified in many tumor types, including but not limited to head and neck, gastroesophageal, breast, genitourinary, cutaneous and colorectal cancers, and has been associated with proliferation, invasion, and metastasis. Alterations in EGFR have also been linked to primary resistance and accelerated tumor growth (designated as hyperprogression) from immune checkpoint inhibitors. However, EGFR amplification and overexpression in tissue have not been well established as reliable biomarkers for anti-EGFR agents for anything other than non-small cell lung cancer (NSCLC). The potential reasons include heterogeneity between primary and metastatic lesions, dynamic changes in genomic alterations that may emerge along with therapeutic pressure or progression, presence of genomic coalterations associated with resistance, and potential differences in response to copy number gain due to aneuploidy versus focal EGFR amplification. 

 

There are two main sample types used for EGFR mutation analysis either tumor tissue using Real Time PCR, Sanger Sequencing or Next Generation Sequencing (NGS) or circulating tumor DNA. 

 

Based on review of the peer reviewed medical literature prior studies looking at the relationship between EGFR amplification and therapeutic response to EGFR inhibitors have shown inconsistent results for patients with a wide range of malignancies. While EGFR amplification/overexpression is associated with cancer aggressiveness, previous studies failed to demonstrate tissue-based assessment of EGFR overexpression to be a reliable biomarker to predict clinical outcomes after anti-EGFR therapies except in non-small cell lung cancer (NSCLC). Current NCCN guidelines for solid tumors do not recommend EGFR mutation analysis except for certain clinical situations for non-small cell lung cancer (NSCLC). 

 

To date, there are various anti-EGFR therapies that are U.S. Food and Drug Administration (FDA) approved, including erlotinib, gefitinib, afatinib, and osimertinib for non–small-cell lung cancer (NSCLC) with specific activating EGFR mutations, and cetuximab and panitumumab for colorectal cancer without KRAS or NRAS mutations.

 

Summary of Evidence 

Because of its critical role in tumor aggressiveness, EGFR has been an attractive target for anticancer therapy in cancers other than non-small cell lung cancer (NSCLC) such as head and neck, gastroesophageal, breast, genitourinary, cutaneous and colorectal cancers. Studies have failed to demonstrate that tissue-based or circulating tumor DNA assessment of EGFR overexpression to be a reliable biomarker to predict clinical outcomes after anti-EGFR therapies except in non-small cell lung cancer (NSCLC). Current NCCN guidelines do not recommend EGFR mutation analysis except for certain clinical situations for non-small cell lung cancer (NSCLC). The evidence is insufficient to determine the effects of the technology on net health outcomes in cancer management except for non-small cell lung cancer (NSCLC), whether performed as an individual test or as part of an expanded panel test. 

 

Practice Guideline and Position Statements

National Comprehensive Cancer Network (NCCN Guidelines

Acute Lymphoblastic Leukemia 1.2021 

Does not include any information regarding testing for EGFR int eh management of acute lymphoblastic leukemia 

 

Acute Myeloid Leukemia 3.2021

Does not include any information regarding testing for EGFR in the management of acute myeloid leukemia 

 

Anal Carcinoma Version 1.2021

Does not include any guidelines related to testing for EGFR in the management of anal carcinoma 

 

Basal Cell Skin Cancer Version 2.2021

Does not include any information regarding testing for EGFR in the management of basal cell skin cancer 

 

B-Cell Lymphomas Version 4.2021

Does not include any information regarding testing for EGFR in the management of B-cell lymphomas 

 

Bladder Cancer Version 3.2021

Does not include any information regarding testing for EGFR in the management of bladder cancer 

 

Bone Cancer Version 1.2021

Does not include any information regarding testing for EGFR in the management of bone cancer

 

Breast Cancer Version 4.2021

Does not include any information regarding testing for EGFR in the management of breast cancer 

 

Central Nervous System Cancers Version 5.2020
Lung Cancer

Systemic treatment options for patients with brain metastases from NSCLC include immunotherapy agents and targeted therapies for cancer that is anaplastic lymphoma kinase (ALK) rearrangement-positive and EGFR mutation – positive 

 

Treatment for Limited Metastatic Lesions

In patients with systemic cancers with options for CNS-active systemic therapies (e.g. ALK or EGFR mutations in NSCLC; BRAF mutations in metastatic melanoma), upfront systemic therapy alone may be considered in carefully selected, asymptomatic patients  

 

Does not include any information regarding testing for EGFR in the management except when related to brain metastases from NSCLC. 

 

Cervical Cancer Version 1.2021

Does not include any information regarding testing for EGFR in the management of cervical cancer.

 

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 4.2021

Does not include any information regarding testing for EGFR in the management of chronic lymphocytic leukemia/small lymphocytic lymphoma

 

Chronic Myeloid Leukemia Version 3.2021

Does not include any information regarding testing for EGFR in the management of chronic myeloid leukemia

 

Colon Cancer Version 2.2021

Does not include any information regarding testing for EGFR in the management of colon cancer 

 

Dermatofibrosarcoma Protuberans Version 1.2021

Does not include any information regarding testing for EGFR in the management of dermatofibrosarcoma protuberans

 

Esophageal and Esophagogastric Junction Cancers Version 2.2021

Does not include any information regarding testing for EGFR in the management of esophageal and esophagogastric junction cancers 

 

Gastric Cancer Version 2.2021

Does not include any information regarding testing for EGFR in the management of gastric cancer

 

Gastrointestinal Stromal Tumors (GISTs) Version 1.2021

Does not include any information regarding testing for EGFR in the management of gastrointestinal stromal tumors (GISTs)

 

Gestational Trophoblastic Neoplasia Version 2.2021

Does not include any information regarding testing for EGFR in the management of gestational trophoblastic neoplasia

 

Hairy Cell Leukemia Version 2.2021

Does not include any information regarding testing for EGFR in the management of hairy cell leukemia

 

Head and Neck Cancers Version 3.2021

Does not include any information regarding testing for EGFR in the management of head and neck cancers 

 

Hepatobiliary Cancers Version 2.2021

Does not include any information regarding testing for EGFR in the management of hepatobiliary cancers

 

Histiocytic Neoplasms Version 1.2021

Does not include any information regarding testing for EGFR in the management of histiocytic neoplasms

 

Hodgkin Lymphoma Version 4.2021

Does not include any information regarding testing for EGFR in the management of Hodgkin lymphoma

 

Kaposi Sarcoma Version 1.2021

Does not include any information regarding testing for EGFR in the management of Kaposi Sarcoma

 

Kidney Cancer Version 4.2021

Does not include any information regarding testing for EGFR in the management of kidney cancer

 

Malignant Pleural Mesothelioma Version 2.2021

Does not include any information regarding testing for EGFR in the management of malignant pleural mesothelioma

 

Melanoma: Cutaneous Version 2.2021

Does not include any information regarding testing for EGFR in the management of cutaneous melanoma 

 

Melanoma: Uveal Version 1.2021

Does not include any information regarding testing for EGFR in the management of uveal melanoma

 

Merkel Cell Carcinoma Version 1.2021

Does not include any information regarding testing for EGFR in the management of merkel cell carcinoma

 

Multiple Myeloma Version 7.2021

Does not include any information regarding testing for EGFR in the management of multiple myeloma

 

Myelodysplastic Syndromes Version 3.2021

Does not include any information regarding testing for EGFR in the management of myelodysplastic syndromes

 

Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes Version 3.2021

Does not include any information regarding testing for EGFR in the management of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes

 

Myeloproliferative Neoplasms Version 1.2021

Does not include any information regarding testing for EGFR in the management of myeloproliferative neoplasms

 

Neuroendocrine and Adrenal Tumors Version 1.2021

Does not include any information regarding testing for EGFR in the management of neuroendocrine and adrenal tumors

 

Occult Primary Version 2.2021

Does not include any information regarding testing for EGFR in the management of occult primary

 

Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 1.2021

Does not include any information regarding testing for EGFR in the management of ovarian cancer including fallopian tube cancer and primary peritoneal cancer

 

Pancreatic Adenocarcinoma Version 2.2021

Does not include any information regarding testing for EGFR in the management of pancreatic adenocarcinoma

 

Pediatric Acute Lymphoblastic Leukemia Version 2.2021

Does not include any information regarding testing for EGFR in the management of pediatric acute lymphoblastic leukemia

 

Pediatric Aggressive Mature B-Cell Lymphomas Version 2.2020

Does not include any information regarding testing for EGFR in the management of pediatric aggressive mature B-cell lymphomas

 

Pediatric Hodgkin Lymphoma Version 3.2021

Does not include any information regarding testing for EGFR in the management of pediatric Hodgkin lymphoma

 

Penile Cancer Version 1.2021

Does not include any information regarding testing for EGFR in the management of penile cancer

 

Primary Cutaneous Lymphomas Version 2.2021

Does not include any information regarding testing for EGFR in the management of primary cutaneous lymphomas

 

Prostate Cancer Version 2.2021

Does not include any information regarding testing for EGFR in the management of prostate cancer

 

Rectal Cancer Version 1.2021

Does not include any information regarding testing for EGFR in the management of rectal cancer

 

Small Bowel Adenocarcinoma Version 1.2021

Does not include any information regarding testing for EGFR in the management of small bowel adenocarcinoma

 

Small Cell Lung Cancer Version 3.2021

Does not include any information regarding testing for EGFR in the management of small cell lung cancer 

 

Small Tissue Sarcoma Version 2.2021

Does not include any information regarding testing for EGFR in the management of small tissue sarcoma

 

Squamous Cell Skin Cancer Version 1.2021

Does not include any information regarding testing for EGFR in the management of squamous cell skin cancer

 

Systemic Light Chain Amyloidosis Version 2.2021

Does not include any information regarding testing for EGFR in the management of systemic light chain amyloidosis

 

Systemic Mastocytosis Version 1.2021

Does not include any information regarding testing for EGFR in the management of systemic mastocytosis 

 

T-Cell Lymphomas Version 1.2021

Does not include any information regarding testing for EGFR in the management of T-cell lymphomas

 

Testicular Cancer Version 2.2021

Does not include any information regarding testing for EGFR in the management of testicular cancer 

 

Thymomas and Thymic Carcinomas Version 1.2021

Does not include any information regarding testing for EGFR in the management of thymomas and thymic carcinomas

 

Thyroid Carcinoma Version 1.2021

Does not include any information regarding testing for EGFR in the management of thyroidcCarcinoma

 

Uterine Neoplasms Version 2.2021

Does not include any information regarding testing for EGFR in the management of uterine neoplasms

 

Vulvar Cancer (Squamous Cell Carcinoma) Version 3.2021

Does not include any information regarding testing for EGFR in the management of vulvar cancer 

 

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Version 1.2021

Does not include any information regarding testing for EGFR in the management of Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Version

 

Wilms Tumor (Nephroblastoma) Version 1.2021

Does not include any information regarding testing for EGFR in the management of Wilms tumor

 

Regulatory Status 

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). 

 

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) (liquid biopsy) for cancer management is available under the auspices of Clinical Laboratory Improvement Amendments.  Laboratories that offer LDTs must be licensed by CLIA for high complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

 

EGFR mutation analysis using Real Time PCR, Sanger Sequencing or Next Generation Sequencing (NGS) are commercially available and these tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA).

 

Prior Approval:

Not applicable

 

Policy:

See Related Medical Policies:

  • 02.04.79 Circulating Tumor DNA for Management of Non-Small Cell Lung Cancer (Liquid Biopsy)
  • 02.04.78 Molecular Analysis for Targeted Therapy of Non-Small Cell Lung Cancer

 

Epidermal Growth Factor Receptor (EGFR) mutation analysis is considered investigational for all indications except for non-small cell lung cancer (NSCLC) whether performed as an individual test or as part of an expanded panel test.

 

Note: For Epidermal Growth Factor Receptor (EGFR) mutation analysis related to non-small cell lung cancer (NSCLC) see the above related medical policies.  

 

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.

  • 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)

 

Selected References:

  • 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.
  • 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
  • National Comprehensive Cancer Network (NCCN) Acute Lymphoblastic Leukemia Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Acute Myeloid Leukemia 3.2021
  • National Comprehensive Cancer Network (NCCN) Anal Carcinoma Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Basal Cell Skin Cancer Version 2.2021
  • National Comprehensive Cancer Network (NCCN) B-cell Lymphomas Version 4.2021
  • National Comprehensive Cancer Network (NCCN) Bladder Cancer Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Bone Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN)  Breast Cancer Version 4.2021
  • National Comprehensive Cancer Network (NCCN) Central Nervous System Cancers Version 5.2020
  • National Comprehensive Cancer Network (NCCN) Cervical Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 4.2021
  • National Comprehensive Cancer Network (NCCN) Chronic Myeloid Leukemia Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Colon Cancer Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Dermatofibrosarcoma Protuberans Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Esophageal and Esophagogastric Junction Cancers Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Gastric Cancer Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Gastrointestinal Stromal Tumors (GISTs) Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Gestational Trophoblastic Neoplasia Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Hairy Cell Leukemia Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Head and Neck Cancers Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Hepatobiliary Cancers Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Histiocytic Neoplasms Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Hodgkin Lymphoma  Version 4.2021
  • National Comprehensive Cancer Network (NCCN) Kaposi Sarcoma Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Kidney Cancer Version 4.2021
  • National Comprehensive Cancer Network (NCCN) Malignant Pleural Mesothelioma Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Melanoma Cutaneous Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Melanoma Uveal Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Merkel Cell Carcinoma Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Multiple Myeloma Version 7.2021
  • National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Myeloproliferative Neoplasms Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Neuroendocrine and Adrenal Tumors Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Occult Primary Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Pancreatic Adenocarcinoma Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Pediatric Acute Lymphoblastic Leukemia Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Pediatric Aggressive Mature B-cell Lymphoma Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Pediatric Hodgkin Lymphoma Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Penile Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Primary Cutaneous Lymphomas Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Primary Cutaneous Lymphomas Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Rectal Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Small Bowel Adenocarcinoma Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Small Cell Lung Cancer Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Small Tissue Sarcoma Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Squamous Cell Skin Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Systemic Light Chain Amyloidosis Version 2.2021
  • National Comprehensive Cancer Network (NCCN) T-Cell Lymphomas Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Testicular Cancer Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Thymomas and Thymic Carcinomas Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Thyroid Carcinoma Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Uterine Neoplasms Version 2.2021
  • National Comprehensive Cancer Network (NCCN) Vulvar Cancer (Squamous Cell Carcinoma) Version 3.2021
  • National Comprehensive Cancer Network (NCCN) Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Wilms Tumor (Nephroblastoma) Version 1.2021

 

Policy History:

  • May 2021 - Annual Review, Policy Revised
  • May 2020 - Annual Review, Policy Renewed
  • September 2019 - Interim Review, Policy Revised
  • 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.