Highmark Commercial Medical Policy - Pennsylvania
Medical Policy: L-164-006
Topic: EGFR Testing for Non-Small Cell Lung Cancer TKI Response
Section: Laboratory
Effective Date: July 1, 2018
Issue Date: July 2, 2018
Last Reviewed: March 2018

Targeted analysis of the EGFR gene can be performed by two different methods:

  • Mutation panels check specifically for the two most common EGFR mutations, E19del and L858R.
  • Sequencing of specific exons will find any mutation in the region (tyrosine kinase domain).

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

EGFR mutation testing may be considered medically necessary in individuals with metastatic non-small cell lung cancer of nonsquamous cell type prior to initiation of treatment with erlotinib, afatinib, or gefitinib therapy.

For patients whose disease progresses either on or after TKI therapy, repeat EGFR testing to identify the emergence of a T790M mutation may be considered medically necessary to determine whether further treatment with osimertinib would be indicated.

Analysis for other mutations within exons 18-24, or other applications related to NSCLC is considered experimental/investigational and therefore, non-covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Procedure Codes
81235

Professional Statements and Societal Positions

The National Comprehensive Cancer Network (NCCN, 2017) guidelines recommend:

  • “Testing for ALK gene rearrangements and EGFR mutations is recommended (category 1) in the NSCLC algorithm for patients with nonsquamous NSCLC or NSCLC not otherwise specified (NOS) so that patients with these genetic abnormalities can received effective treatment with targeted agents such as erlotinib, gefitinib, afatinib, and crizotinib.”
  • “Although rare, patients with ALK rearrangements or EGFR mutations can have mixed squamous histology. Therefore, testing for ALK rearrangements, ROS1 rearrangements, and EGFR mutations can be considered in patients with squamous cell histology if they are never smokers, small biopsy specimens were used for testing, or mixed histology was reported. EGFR, KRAS, ROS1, and ALK genetic alterations do not usually overlap.”
  • “Testing should be conducted as part of broad molecular profiling.”
  • “The NCCN NSCLC Guidelines Panel strongly endorses broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.”
  • “In patients with squamous cell carcinoma, the observed incidence of EGFR mutations is 2.7% with a confidence that the true incidence of mutations is less than 3.6%. This frequency of EGFR mutations does not justify routine testing of all tumor specimens.”

The National Comprehensive Cancer Network (NCCN, 2017) states the following in regards to liquid biopsies for EGFR T790M testing in patients with non-small cell lung cancer:

  • In patients with a sensitizing EGFR mutation at progression, tissue biopsy testing for EGFR T790M testing should be performed.
  • “Recent data suggest that plasma genotyping (also known as liquid biopsy or plasma biopsy) may be considered instead of tissue biopsy to detect whether patients have T790M; however, if the plasma biopsy is negative, then tissue biopsy is recommended if feasible.”

The American Society of Clinical Oncology (ASCO, 2011) provisional clinical opinion states that:

  • "On the basis of the results of five phase III RCTs, patients with advanced NSCLC of the lung who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first line therapy."

The College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (CAP/IASLC/AMP) Guidelines state:

  • “EGFR molecular testing should be used to select patients for EGFR targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics.”
  • “EGFR and ALK testing is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade. In the setting of fully excised lung cancer specimens, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component…”
  • “For patients with multiple, apparently separate, primary lung adenocarcinomas, each tumor may be tested but testing of multiple different areas within a single tumor is not necessary.”
  • In the setting of more limited lung cancer specimens (eg, biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR and ALK testing may be performed in cases showing squamous cell histology. Clinical criteria (eg, young age, lack of smoking history) may be useful to select a subset of these samples for testing.”

The American Society of Clinical Oncology (ASCO, 2011) provisional clinical opinion states that:

  • "On the basis of the results of five phase III RCTs, patients with advanced NSCLC of the lung who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or anEGFR TKI) should have their tumor tested for EGFR mutations todetermine whether an EGFR TKI or chemotherapy is the appropriate firstline therapy."
  • EGFR is listed as an FDA-approved biomarker for both erlotinib and afatinib.
  • Product labeling for erlotinib, afatinib, and gefitinib address EGFR testing. All three products are listed as “first line treatments for patients with metastatic non-small cell lung cancer whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.”
  • Product labeling for osimertinib notes the product is “a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.”

Place of Service: Inpatient/Outpatient

Experimental/Investigational (E/I) services are not covered regardless of place of service.

EGFR Testing for Non-Small Cell Lung Cancer TKI Response is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

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Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.

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