Notification Issue Date:

Policy Attachment

Attachment to Policy # 06.02.30e


Policy #:06.02.30e

Description:KRAS mutation analylsis to predict treatment response to elotinib (Tarceva®) in non-small cell lung cancer (NSCLC)

Title:Pharmacogenetic Testing to Determine Drug Sensitivity (AmeriHealth Administrators)


KRAS Mutation Analysis in Non-Small Cell Lung Cancer

Epidermal growth factor receptor (EGFR) has emerged as a leading target for molecular-based therapy in non-small cell lung cancer (NSCLC) because EGFR overexpression has been associated with poor prognosis, advanced stage, and/or resistance to therapy. Overexpression of EGFR is seen in large numbers of NSCLC tumor specimens. Small-module EGFR tyrosine kinase inhibitors (TKIs), such as erlontinib and gefitinib, have been developed for use in individuals with previously treated advanced NSCLC. Clinical evidence suggests that the benefit from these TKIs may be limited to a subgroup of individuals with NSCLC. Biomarkers are being evaluated to aid in assisting clinicians to find who will benefit from treatment with EGFR TKI inhibitors.

One of the biomarkers that is being investigated as a negative prognostic indicator is the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of signaling from the EGF receptor, possibly rendering a tumor resistant to therapies that target the EGF receptor (e.g., TKIs). KRAS mutations are found in approximately 15% to 30% of lung adenocarcinomas.

Two TKIs are used for treatment of NSCLC:

1) Erlontinib (Tarceva®) was approved by the US Food and Drug Administration in 2004 as salvage therapy for advanced NSCLC due to the results of a Phase II trial, which showed a modest survival benefit when compared to placebo.

2) Gefitinib (Iressa®) was given FDA approval in 2003 via the accelerated approval process, based on the initially promising results from Phase II trials. The labeling was limited to those with NSCLC who had failed two or more prior chemotherapy regimens. In 2004, however, the results of Phase II trials became available, which suggested that there was no survival benefit associated with gefitinib (Iressa®). In response, the FDA, in 2005, revised the labeling to indicate that gefitinib (Iressa®) should be used only in those patients who were currently benefitting from the agent, or who had benefitted from it previously, and that no new individuals were to be given the drug.

While gefitinib (Iressa®) had limited use in the US since 2005, it was still being used outside of the US and a study was published that evaluated the use of gefitinib (Iressa®) in 24 of these countries. Study subjects (1433 who were evaluable) included those who had advanced or metastatic disease and who had been previously treated with at least one platinum-containing regimen; participants were randomly assigned to receive docetaxel or gefitinib (Iressa®). Both groups had similar progression-free survival (PFS) and overall survival (OS) based on objective tumor response, but, those in the gefitinib (Iressa®) group had fewer adverse events than those in the docetaxel group. Whether or not gefitinib (Iressa®) will become available in the US remains unknown at this time.

National Comprehensive Cancer Network (NCCN) Guidelines

NCCN guidelines state that patients with NSCLC whose tumors harbor KRAS mutations should be considered for therapy other than erlotinib.


Coverage is subject to the terms, conditions, and limitations of the member's contract.

KRAS mutation analylsis to predict treatment response to erlotinib (Tarceva®) in non-small-cell lung cancer (NSCLC) is considered medically necessary and, therefore, covered as a technique to predict treatment response to erlotinib (Tarceva®) in non-small-cell lung cancer.


The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.


Subject to the terms and conditions of the applicable benefit contract, enetic testing for somatic mutations of the KRAS gene to predict treatment response to erlotinib (Tarceva®) in non-small cell lung cancer is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.


Genetic testing is a laboratory procedure and is historically not regulated by the US Food and Drug Administration (FDA). Clinical Laboratory Improvement Amendments (CLIA) establishes quality standards for all laboratory testing. However, recently, the FDA is reported to be involved in the evaluation of the service of genetic testing.


Blue Cross Blue Shield Association. Technology Evaluation Center. 2008 TEC Assessments. KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer.

Boldrini L, Ali G, Gisfredi S, et al. Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study. Oncol Rep. 2009;22(4):683-91.

Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23(25):5900-9.

Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res. 2006;12(20):6049-55.

Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23(25):5856-8.

Jackman DM, Yeap BY, Lindeman NI, et al. Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol. 2007;25(7):760-6.

Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomized phase III trial. Lancet. 2008;372(9652):1809-18.

Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008;26(9):1472-8.

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. (v.3.2011). Available at: Accessed July 31, 2013.

Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2(1):57-61.

Schneider CP, Heigener D, Schott-von-Romer K, et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer. J Thorac Oncol. 2008;3(12):1446-53.

Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123-32.

Toschi L, Cappuzzo F. Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist. 2007;12(2):211-20.

Zhu CQ, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008;26(26):4268-75.

Coding Table

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

Code System
Code Number and Code Narrative
CPT 81275



ICD-10 Procedure N/A
ICD-10 Diagnosis N/A
HCPCS G0452 Molecular pathology procedure; physician interpretation and report

Version Effective Date: 07/01/2016
Version Issued Date: 07/01/2016
Version Reissued Date: 10/10/2019

© 2017 AmeriHealth.