Notification



Notification Issue Date:



Policy Attachment

Attachment to Policy # MA06.008b


Attachment:H

Policy #:MA06.008b

Description:Epidermal Growth Factor (EGFR) Mutation Analysis for individuals with non-small cell lung cancer

Title:Pharmacogenetic Testing to Determine Drug Sensitivity

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.


Title: Epidermal Growth Factor (EGFR) Mutation Analysis for Individuals with Non-Small-Cell Lung Cancer (NSCLC)


POLICY

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

MEDICALLY NECESSARY

Analysis of 2 types of somatic mutation within the EGFR gene—small deletions in exon 19 and a point mutation in exon 21 (L858R)—is considered medically necessary and, therefore, covered to predict treatment response to erlotinib (Tarcevaź) in individuals with advanced NSCLC of nonsquamous cell type.

EXPERIMENTAL/INVESTIGATIONAL

Analysis of two types of somatic mutation within the EGFR gene—small deletions in exon 19 and a point mutation in exon 21 (L858R)—is considered experimental/investigational and, therefore, not covered for individuals with advanced NSCLC of squamous cell-type because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

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

REQUIRED DOCUMENTATION

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.

POLICY GUIDELINES

There is no Medicare coverage determination addressing this service; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, epidermal growth factor (EGFR) mutation analysis in NSCLC to predict treatment response to erlotinib (Tarcevaź) is not eligible for payment under the medical benefits of the Company's Medicare Advantage products because the service is considered experimental/investigational.

Services that are experimental/investigational are excluded from the Company's Medicare Advantage products. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

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.

DESCRIPTION

The leading cause of cancer-related death in the United States among men and women is lung cancer; the five-year survival rate is only 15%, which includes all stages of lung cancer. There are two main types of lung cancer: non-small-cell lung cancer (NSCLC), accounting for greater than 80% of lung cancer cases, and small cell lung cancer (SCLC), accounting for the remainder of cases. Under the overarching heading of NSCLC, there are three distinct subtypes: squamous cell carcinoma, adenocarcinoma, and large-cell undifferentiated carcinoma.

Epidermal growth factor receptor (EGFR) is involved with regulating the growth of normal cells and some types of cancer cells. In some types of tumors, including NSCLC, EGFR overexpression is associated with poor prognosis, advanced age, and/or resistance to therapy. The EGFR has become a leading target for molecular-based therapy. EGFR tyrosine kinase inhibitors (TKIs), such as geftinib and erlotinib, are FDA-approved for the treatment of NSCLC, and there is a body of clinical data that suggests that the efficacy of these drugs in NSCLC may be limited to a subgroup of patients. Biomarkers are being evaluated to select the right subset of individuals who are more likely to have a response to TKI drug therapy.

The analyses speaking to the correlation between the presence of EGFR gene TK domain mutations and response to TKI agents, or absence of this type of mutation and non-response to TKI drugs, consist of nonconcurrent and retrospective analyses. Although this set of data suggests an association between the mutations and responsiveness, there were some individuals who did not have a mutation but who responded to a TKI, and vice versa. This limitation raises questions regarding the clinical application of this strategy when it comes to making therapeutic decisions. Some phase II studies suggest clinical validity of EGFR mutation analysis as a predictor of NSCLC response to TKI therapy with acceptable positive predictive value (PPV); however, prospective data establishing a high negative predictive value (NPV) for this mutational analysis is lacking. In clinical practice, where all patients would receive TKI therapy for endstage disease, the NPV has greater clinical utility than the PPV.

Overall, a substantial body of published evidence supports a conclusion that the presence of a tumor tissue somatic mutation within exons 18-24 of the TK domain of the EGFR gene is a fairly robust predictor of objective response to TKI therapy in patients with advanced NSCLC.

The National Comprehensive Cancer Network (NCCN) in the V1.2013 guidelines on non-small-cell lung cancer recommends EGFR mutational analysis in individuals with advanced NSCLC. It does suggest testing be deferred in individuals with squamous cell carcinomas because of the low incidence of mutation in this histopathology type, except in never smokers and small biopsy specimens.

In a 2011 publication, the American Society of Clinical Oncology (ASCO) issued a provisional clinical opinion on EGFR mutation testing for individuals with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. It concludes individuals with NSCLC being considered for first-line therapy with an EGFR tyrosine kinase inhibitor should have their tumor tested for EGFR mutations to determine whether an EGFR tyrosine kinase inhibitor or chemotherapy is the appropriate first-line therapy.

Two randomized controlled trials, non-concurrent prospective studies, and single-arm enrichment studies demonstrate that the detection of epidermal growth factor receptor (EGFR) gene mutations identifies individuals who are likely to benefit from use of erlotinib and who therefore represent ideal candidates for treatment with this drug. These observations have been made in a population composed primarily of tumors with adenocarcinoma histology. There is currently no evidence to indicate whether this behavior is also seen in individuals with squamous cell histology.

Individuals who are found to have wild-type tumors are unlikely to respond to erlotinib. They should be considered candidates for alternative proven therapies based upon clinical guidelines and established evidence.

REFERENCES

Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006;95(8):998-1004.

Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005;23(31):8081-92

Blue Cross Blue Shield Association. Technology Evaluation Center. 2007 TEC Assessments; Epidermal Growth Factor Receptor Mutations and Tyrosine Kinase Inhibitor Therapy in advanced non-small cell lung cancer. November 2007; Volume 22, Number 6.

Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97(9):643-55.

Chou TY, Chiu CH, Li LH, et al. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res. 2005;11(10):3750-7.

Cortes-Funes H, Gomez C, Rosell R, et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol. 2005;16(7):1081-6.

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.

Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005;23(11):2493-501.

Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol. 2006;24(31):5034-42.

Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004;10(24):8195-203.

Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 2006;24(21):3340-6.

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):2121-7.

Kim KS, Jeong JY, Kim YC, et al. Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res. 2005;11(6):2244-51.

Kondo M, Yokoyama T, Fukui T, et al. Mutations of epidermal growth factor receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery. Lung Cancer. 2005;50(3):385-91.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-39.

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

Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 2005;23(11):2513-20.

Mu XL, Li LY, Zhang XT, et al. Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in Chinese patients with non-small cell lung cancer. Clin Cancer Res. 2005;11(12):4289-94.

Niho S, Kubota K, Goto K, et al. First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol. 2006;24(1):64-9.

National Comprehensive Cancer Network (NCCN). NCCN Guidelines: Non-small cell lung cancer. 2012. Version 1.2013. Available oneline at http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed July 31, 2013.

Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-500.

Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101(36):13306-11.

Petrelli F, Borgonovo K, Cabiddu M, et al. Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell-lung cancer: a meta-analysis of 13 randomized trials. Clin Lung Cancer 2011.

Rosell R, Ichinose Y, Taron M et al. Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer. Lung Cancer. 2005;50(1):25-33.

Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012; 13(3):239-46.

Satouchi M, Negoro S, Funada Y, et al. Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib. Br J Cancer. 2007;96(8):1191-6.

Sequist LV, Joshi VA, Janne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007;12(1):90-8.

Sone T, Kasahara K, Kimura H, et al. Comparative analysis of epidermal growth factor receptor mutations and gene amplification as predictors of gefitinib efficacy in Japanese patients with nonsmall cell lung cancer. Cancer. 2007;109(9):1836-44.

Sunaga N, Tomizawa Y, Yanagitani N, et al. Phase II prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small cell lung cancer with EGFR mutations, irrespective of previous chemotherapy. Lung Cancer. 2007;56(3):383-9

Sutani A, Nagai Y, Udagawa K, et al. Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp. Br J Cancer. 2006;95(11):1483-9.

Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005;23(28):6829-37.

Taron M, Ichinose Y, Rosell R, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res. 2005;11(16):5878-85.

Tokumo M, Toyooka S, Kiura K, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res. 2005;11(3):1167-73.

Tomizawa Y, Iijima H, Sunaga N, et al. Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer. Clin Cancer Res. 2005;11(19 Pt 1):6816-22.

Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer: molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-44.

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.

Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol. 2007;2(1):22-8.

Zhang XT, Li LY, Mu XL, et al. The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer. Ann Oncol. 2005;16(8):1334-42.

Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12(8):735-42.


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
CPT81235
HCPCSG0452 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

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