Notification



Notification Issue Date:



Medical Policy Bulletin


Title:VeriStrat® Testing for Targeted Therapy in Non-Small Cell Lung Cancer

Policy #:06.02.49b

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin 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 Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

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

MEDICALLY NECESSARY

VeriStrat® serum proteomic testing is considered medically necessary and, therefore, covered for an individual with advanced non-small cell lung cancer (NSCLC) to determine second-line treatment when all of the following criteria are met:
  • EGFR mutation status is wildtype (i.e., no mutation detected) or unknown
  • Individual has failed first-line systemic chemotherapy
  • Erlotinib (Tarceva®) therapy is planned
  • Test results will be used to decide whether to proceed with erlotinib (Tarceva®) therapy

EXPERIMENTAL/INVESTIGATIONAL

All other uses for VeriStrat® serum proteomic testing are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness 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.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, VeriStrat® testing for targeted therapy 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.

Description

Lung cancer is the leading cause of cancer death in the United States, with an estimated 224,210 new cases and 159,260 deaths due to the disease in 2014. Non-small cell lung cancer (NSCLC), which includes nonsquamous carcinoma (adenocarcinoma, large-cell carcinoma, and other cell types) and squamous cell carcinoma, causes about 85% of lung cancer cases. Treatment approaches generally include surgery, radiotherapy, and chemotherapy, either alone or in combination, depending on the disease stage and tumor characteristics.

However, in up to 85% of cases, the cancer has spread locally beyond the lungs at diagnosis, precluding surgical eradication, and up to 40% of patients with NSCLC present with metastatic disease. When treated with standard platinum-based chemotherapy, patients with advanced NSCLC have brief responses, with a median time to progression of 3 to 5 months. Second-line chemotherapy after platinum-based chemotherapy is associated with small improvements in time to progression. However, genetic abnormalities in NSCLC and the development of therapies targeted to those abnormalities have prompted interest in tests to predict response to targeted therapies.

GENETIC ALTERATIONS IN NSCLC

Several common genetic alterations in NSCLC have been targets for drug therapy, the most well-established of which is the use of tyrosine kinase inhibitors (TKIs) targeting the EGFR.

EGFR MUTATIONS IN NSCLC

The EGFR, a receptor tyrosine kinase (TK), is frequently overexpressed and activated in NSCLC. Drugs that inhibit EGFR signaling either prevent ligand binding to the extracellular domain (monoclonal antibodies) or inhibit intracellular TK activity (small molecule TKIs). These targeted therapies dampen signal transduction through pathways downstream to the EGF receptor, such as the RAS/RAF/MAPK cascade. RAS proteins are G-proteins that cycle between active and inactive forms in response to stimulation from cell surface receptors such as EGFR, acting as binary switches between cell surface EGFR and downstream signaling pathways. These pathways are important in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization. Mutations in 2 regions of the EGFR gene, including small deletions in exon 19 and a point mutation in exon 21 (L858R) appear to predict tumor response to TKIs such as erlotinib. The prevalence of EGFR mutations in NSCLC varies by population, with the highest prevalence in nonsmoking, Asian women, with adenocarcinoma, in whom EGFR mutations have been reported to be up to 30% to 50%. The reported prevalence of EGFR mutations in lung adenocarcinoma patients in the United States is approximately 15%.

ALK MUTATIONS IN NSCLC

In about 2% to 7% of NSCLC patients in the United States, tumors express a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene (EML4-ALK), which is created by an inversion on chromosome 2p. The EML4 fusion leads to ligand-independent activation of ALK, which encodes a receptor TK whose precise cellular function is not completely understood. EML4-ALK mutations are more common in never-smokers or light smokers and tend to be associated with younger age of NSCLC onset, and typically do not occur in conjunction with EGFR mutations. Testing for the ALK-EML4 fusion gene in patients with adenocarcinoma-type NSCLC is used to predict response to the small molecule TKI crizotinib.

EGFR-SELECTIVE SMALL MOLECULE TKIs

Three orally administered EGFR-selective small molecule TKIs have been identified for use in treating NSCLC: gefitinib (Iressa®, AstraZeneca), erlotinib (Tarceva®, OSI Pharmaceuticals), and afatinib (Gilotrif™, Boehringer Ingelheim). Only erlotinib and afatinib are approved by the Food and Drug Administration (FDA); although originally FDA approved, in 2004, a phase 3 trial suggested gefitinib was not associated with a survival benefit. In May 2005, the FDA revised gefitinib labeling, further limiting its use to patients who had previously benefitted or were currently benefiting from the drug; no new patients were to be given gefitinib. A 2013 meta-analysis of 23 trials of erlotinib, gefitinib, and afatinib in patients with advanced NSCLC reported improved progression-free survival (PFS) in EGFR mutation-positive patients treated with EGFR TKIs in the first- and second-line settings and for maintenance therapy. Comparisons were with chemotherapy, chemotherapy and placebo, and placebo in the first-line, second-line, and maintenance therapy settings, respectively. Among EGFR mutation-negative patients, PFS was improved with EGFR TKIs compared with placebo for maintenance therapy but not in the first- and second-line settings. Overall survival (OS) did not differ between treatment groups in either mutation-positive or mutation-negative patients. Statistical heterogeneity was not reported for any outcome. The authors concluded that EGFR mutation testing is indicated to guide treatment selection in NSCLC patients. On the basis of the results of five phase 3 randomized controlled trials, the American Society of Clinical Oncology recommends that patients with NSCLC 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 primary role for TKIs in NSCLC is for EGFR mutation-positive patients with advanced NSCLC. The use of TKIs in NSCLC in EGFR mutation-negative patients is controversial.

ANTI-EGFR MONOCLONAL ANTIBODIES

For the treatment of KRAS-mutated NSCLC, anti-EGFR monoclonal antibodies have been investigated as possible treatment options. Anti-EGFR monoclonal antibodies include cetuximab and panitumumab. Cetuximab may be used in combination with chemotherapy in patients with advanced or recurrent NSCLC as first-line and maintenance therapy. Panitumumab is not generally used in NSCLC.

OTHER TARGETED THERAPIES

Crizotinib is a novel MET-, ROS-1-, and ALK-TKI, which is associated with improved PFS in patients with advanced NSCLC that is ALK gene rearrangement-positive. Crizotinib is considered first-line therapy for advanced ALK-positive lung adenocarcinoma. Other ALK-TKIs, such as ceritinib, are under investigation. Proposed targeted therapies for other genetic alterations in NSCLC are trastuzumab for HER2 mutations, crizotinib for MET amplification and ROS-1 rearrangement, vemurafenib and dabrafenib for BRAF mutations
and cabozantinib for RET rearrangements.

PROTEOMICS TESTING IN SELECTING TARGETED TREATMENT FOR NSCLC

Proteomic testing has been proposed as a way to predict outcomes and response to and selection of targeted therapy for patients with non-small cell lung cancer (NSCLC). One commercially available test, the VeriStrat® assay VeriStrat® (Biodesix Inc., Boulder, CO), has been investigated as a predictive marker for response to EGFR tyrosine kinase inhibitors (TKIs).

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 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.

For NSCLC, 1 commercially available serum-based test, VeriStrat® (Biodesix Inc., Boulder, CO) has been developed that is proposed to predict response to TKIs. The test relies on a predictive algorithm based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) analysis of pretreatment serum to generate a “good” or “poor” assessment for response to TKIs. VeriStrat has been proposed as a method to predict response to erlotinib in patients with NSCLC after failure of treatment with first-line therapy. Proposed uses have been in addition to EGFR testing, or in patients who do not have tumor samples available for EGFR testing. Although the VeriStrat MALDI-MS-based predictive algorithm has the largest body of literature associated with it, other investigators have used alternative MS methods, such as surface-enhanced laser desorption ionization/time-of-flight (SELDI/TOF) mass spectrometry, and alternative predictive algorithms, in the assessment of proteomic predictors of lung cancer risk.

National Comprehensive Cancer Network (NCCN) guidelines on non-small cell lung cancer (NCCN, 2015) recommend proteomic testing for patients with NSCLC and wild-type EGFR or with unknown EGFR status. The guidelines state that a patient with a “poor” classification should not be offered erlotinib in the second-line setting. For support, NCCN guidelines reference a study by Gregorc, et al. (2014), who reported that serum protein test status (Veristrat) is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting, and that patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small cell lung cancer were enrolled in 14 centrers in Italy. Patients were stratified according to a minimization algorithm by Eastern Cooperative Oncology Group performance status, smoking history, center, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m2, intravenously, every 21 days, or docetaxel 75 mg/m2, intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population.  Investigators randomly assigned 142 patients to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. The investigators noted a significant interaction between treatment and proteomic classification (pinteraction = 0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). The investigators found that patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08–2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77–1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs 1 [less than 1%] in the erlotinib group), whereas skin toxicity (one [less than 1%] vs 22 [16%]) was the most frequent in the erlotinib group.
References


Akerley W, Boucher K, Rich N, et al. A phase II study of bevacizumab and erlotinib as initial treatment for metastatic non-squamous, non-small cell lung cancer with serum proteomic evaluation. Lung Cancer. 2013;79(3):307-311.

Akerley WL, Nelson RE, Cowie RH, et al. The impact of a serum based proteomic mass spectrometry test on treatment recommendations in advanced non-small-cell lung cancer. Curr Med Res Opin. 2013;29(5):517-525.

Amann JM, Lee JW, Roder H, et al. Genetic and proteomic features associated with survival after treatment with erlotinib in first-line therapy of non-small cell lung cancer in Eastern Cooperative Oncology Group 3503. J Thorac Oncol. 2010;5(2):169-178.

Carbone DP, Ding K, Roder H, et al. Prognostic and predictive role of the VeriStrat plasma test in patients with advanced non-small-cell lung cancer treated with erlotinib or placebo in the NCIC Clinical Trials Group BR.21 trial. J Thorac Oncol. 2012;7(11):1653-1660.

Carbone DP, Salmon JS, Billheimer D, et al. VeriStrat classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumab. Lung Cancer. 2010;69(3):337-340.

College of American Pathologists, International Association for the Study of Lung Cancer, Association for Molecular Pathology (CAP,IASLC, AMP),. Molecular testing guidelines for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. 2013;
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed August 26, 2014.

Gautschi O, Dingemans AM, Crowe S, et al. VeriStrat(R) has a prognostic value for patients with advanced nonsmallcell lung cancer treated with erlotinib and bevacizumab in the first line: pooled analysis of SAKK19/05 and NTR528. Lung Cancer. 2013;79(1):59-64.

Gregorc V, Novello S, Lazzari C, et al. Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial. Lancet Oncol. 2014;15(7):713-721.

Jacot W, Lhermitte L, Dossat N, et al. Serum proteomic profiling of lung cancer in high-risk groups and determination of clinical outcomes. J Thorac Oncol. 2008;3(8):840-850.

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):2121-2127.

Kuiper JL, Lind JS, Groen HJ, et al. VeriStrat((R)) has prognostic value in advanced stage NSCLC patients treated with erlotinib and sorafenib. Br J Cancer. 2012;107(11):1820-1825.

Lazzari C, Spreafico A, Bachi A, et al. Changes in plasma mass-spectral profile in course of treatment of nonsmall cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors. J Thorac Oncol. 2012;7(1):40-48.

Lee CK, Brown C, Gralla RJ, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst. 2013;105(9):595-605.

Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823-859.

National Comprehensive Cancer Network (NCCN). Non-small cell lung cancer V5.2015. 2015;
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed August 25, 2015.

Nelson RE, Stenehjem D, Akerley W. A comparison of individualized treatment guided by VeriStrat with standard of care treatment strategies in patients receiving second-line treatment for advanced non-small cell lung cancer: A cost-utility analysis. Lung Cancer. 2013;82(3):461-468.

Novitas Solutions. Local Coverage Article: Biomarkers for Oncology (A52317). 2014; http://www.novitas-solutions.com/webcenter/faces/oracle/webcenter/page/scopedMD/sad78b265_6797_4ed0_a02f_81627913bc78/Page57.jspx?contentId=00027177&_afrLoop=3868279503053000#!%40%40%3F_afrLoop%3D3868279503053000%26contentId%3D00027177%26_adf.ctrl-state%3Dit1k1pnpi_4. Accessed September, 2014.

Research OoCCP. What is Cancer Proteomics? http://proteomics.cancer.gov/. Accessed September, 2014.

Salmon S, Chen H, Chen S, et al. Classification by mass spectrometry can accurately and reliably predict outcome in patients with non-small cell lung cancer treated with erlotinib-containing regimen. J Thorac Oncol. 2009;4(6):689-696.

Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-2394.

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):123-132.

Socinski MA, Evans T, Gettinger S, et al. Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e341S-368S.

Stinchcombe TE, Roder J, Peterman AH, et al. A retrospective analysis of VeriStrat status on outcome of a randomized phase II trial of first-line therapy with gemcitabine, erlotinib, or the combination in elderly patients (age 70 years or older) with stage IIIB/IV non-small-cell lung cancer. J Thorac Oncol. 2013;8(4):443-451.

Sun W, Hu G, Long G, et al. Predictive value of a serum-based proteomic test in non-small-cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors: a meta-analysis. Curr Med Res Opin. 9 2014:1-7.

Taguchi F, Solomon B, Gregorc V, et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst. 2007;99(11):838-846.

Wu X, Liang W, Hou X, et al. Serum proteomic study on EGFR-TKIs target treatment for patients with NSCLC. Onco Targets Ther. 2013;6:1481-1491.





Coding

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.

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

CPT Procedure Code Number(s)

81538


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

C34.00 Malignant neoplasm of unspecified main bronchus

C34.01 Malignant neoplasm of right main bronchus

C34.02 Malignant neoplasm of left main bronchus

C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung

C34.11 Malignant neoplasm of upper lobe, right bronchus or lung

C34.12 Malignant neoplasm of upper lobe, left bronchus or lung

C34.2 Malignant neoplasm of middle lobe, bronchus or lung

C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung

C34.31 Malignant neoplasm of lower lobe, right bronchus or lung

C34.32 Malignant neoplasm of lower lobe, left bronchus or lung

C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung

C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung

C34.82 Malignant neoplasm of overlapping sites of left bronchus and lung

C34.90 Malignant neoplasm of unspecified part of unspecified bronchus or lung

C34.91 Malignant neoplasm of unspecified part of right bronchus or lung

C34.92 Malignant neoplasm of unspecified part of left bronchus or lung



HCPCS Level II Code Number(s)

N/A


Revenue Code Number(s)

N/A

Coding and Billing Requirements



Policy History

Revisions from 06.02.49b
08/29/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on VeriStrat® Testing for Targeted Therapy in Non-Small Cell Lung Cancer.


Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date: 05/06/2016
Version Issued Date: 05/06/2016
Version Reissued Date: 08/29/2018

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