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Proteomic Testing for Systemic Therapy in Non-Small Cell Lung Cancer

Policy Number: MP-570

Latest Review Date: December 2020

Category: Laboratory

Policy Grade: B

POLICY:

The use of proteomic testing, including but not limited to the VeriStrat® assay, is considered not medically necessary and investigational for all uses in the management of non-small cell lung cancer.

DESCRIPTION OF PROCEDURE OR SERVICE:

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

Non-Small-Cell Lung Cancer

Lung cancer is the leading cause of cancer death in the United States, with an estimated 228,150 new cases and 142,670 deaths due to the disease in 2019. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and includes nonsquamous carcinoma (adenocarcinoma, large cell carcinoma, other cell types) and squamous cell carcinoma.

Diagnosis

The stage at which lung cancer is diagnosed has the greatest impact on prognosis. Localized disease confined to the primary site has a 55.6% relative five-year survival but accounts for only 16% of lung cancer cases at diagnosis. Mortality increases sharply with advancing stage. Metastatic lung cancer has a relative 5-year survival of 4.5%. Overall, advanced disease; defined as regional involvement and metastatic account for approximately 80% of cases of lung cancer at diagnosis. These statistics are mirrored for the population of NSCLC with 85% of cases presenting as advances disease and up to 40% if patients with metastatic disease.

In addition to tumor stage; age, sex, and performance status are independent prognostic factors for survival particularly in early-stage disease. Wheatley-Price et al (2010) reported on a retrospective pooled analysis of 2,349 advanced NSCLC patients from five randomized chemotherapy trials. Women had a higher response rate to platinum-based chemotherapy than men. Greater overall survival (OS) than men were among those with adenocarcinoma histology. A small survival advantage exists for squamous cell carcinoma over non-bronchiolar nonsquamous histology.

The oncology clinical care and research community use standard measures of performance status: Eastern Cooperative Oncology Group scale and Karnofsky Performance Scale.

Treatment

Treatment approaches are multimodal and generally include surgery, radiotherapy, and chemotherapy (either alone or in combination with another treatment, depending on disease stage and tumor characteristics). Per the National Comprehensive Cancer Network (NCCN) guidelines, the clinical management pathway for stage I or II NSCLC is dependent on surgical findings and may involve resection, radiotherapy, chemotherapy, or chemoradiation. First-line chemotherapy regimens for neoadjuvant and adjuvant therapy utilize platinum-based agents (e.g., cisplatin, carboplatin) in combination with other chemotherapeutics and/or radiotherapy. Treatment recommendations are based on the overall health or performance status of the patient, presence or absence of metastases, as well as the presence or absence of a treatment-sensitizing genetic variant. These aspects inform the selection of targeted and systemic therapies.

For patients who experience disease progression following initial systemic therapy, subsequent treatment regimens are recommended, mainly featuring novel programmed death-ligand 1 (PD-L1) inhibitors. For patients with sensitizing epidermal growth factor receptor (EGFR) mutations, recommendations include first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) afatinib, erlotinib, dacomitinib, gefitinib, or osimertinib and subsequent therapy with osimertinib. The NCCN does not make any recommendations for the use of EGFR TKIs in the absence of a confirmed sensitizing EGFR mutation. For patients with progression on TKIs other than osimertinib, testing for T790M is recommended, however, switching to osimertinib can be considered regardless of mutational status. Osimertinib carries a Category 1 recommendation for T790M+ patients with disease progression on an alternative EGFR TKI. For progression on osimertinib with limited and/or isolated lesions, a continuation of osimertinib and definitive local therapy via surgery, stereotactic ablative radiotherapy (SABR), or stereotactic radiosurgery (SRS) is recommended. Initial systemic therapy recommendations can be considered for multiple, symptomatic, systemic lesions.

Genomic Alterations

Several common genetic alterations in NSCLC have been targets for drug therapy, the most well-established of which are tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) and crizotinib targeting the anaplastic lymphoma kinase (ALK) gene rearrangement.

EGFR Variants

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 EGFR, 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.  Further, RAS proteins act as binary switches between cell surface EGFR and downstream signaling pathways and those pathways play a crucial role in cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

Variants in two regions of the EGFR gene, including small deletions in exon 19 and a point variant in exon 21 (L858R) appear to predict tumor response to tyrosine kinase inhibitors (TKIs) such as erlotinib. The prevalence of EGFR variants in NSCLC varies by population, with the highest prevalence in non-smoking, Asian women, with adenocarcinoma; for that subpopulation, EGFR variants have been reported to be as high as 30%-50%. The reported prevalence of EGFR variants in lung adenocarcinoma patients in the U.S. is approximately 15%.

ALK Variants

In 2% to 7% of NSCLC patients in the US, tumors express a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) 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 variants are more common in never-smokers or light smokers, tend to be associated with younger age of NSCLC onset, and typically do not occur in conjunction with EGFR variants.

Testing for the EML4-ALK fusion gene in patients with adenocarcinoma-type NSCLC is used to predict response to the small molecule TKI crizotinib.

Other Genetic Variants

Other genetic variants, identified in subsets of patients with NSCLC, are summarized in the table below. The role of testing for these variants to help select targeted therapies for NSCLC is less well-established than for EGFR variants.

Table. Non-EFGR Variants in NSCLC

Gene

Gene Function

Estimated Variants Prevalence in NSCLC

Patient and Tumor Characteristics

KRAS

Encodes RAS proteins; mutations associated with constitutively-activated protein.

20-30%

Adenocarcinomas

Heavy smokers

ALK

Encodes a receptor TK in the insulin receptor family.

4-5%

Never smokers

Male

Advanced disease

ROS1

Encodes a receptor tyrosine kinase in the insulin receptor family.

0.9-3.7%

Adenocarcinomas

Never smokers

RET

Proto-oncogene that encodes a receptor tyrosine kinase growth factor.

0.6-2%

 

MET

Oncogene that encodes a receptor tyrosine kinase that is activated in response to binding of hepatocyte growth factor.

2-4% of previously-untreated NSCLC; 5-20% of patients with acquired resistance to EGFR TKIs

Patients with acquired resistance to EGFR TKIs

BRAF

Serine-threonine kinase downstream from RAS in RAS-RAF-ERK-MAPK pathway

1-3% of adenocarcinomas

Heavy smokers

HER

HER (EGFR) family of TK receptors; dimerizes with EGFR family members when activated.

1-2% of NSCLC

Adenocarcinomas

Nonsmoking women

PIK3CA

Intracellular signaling pathway

~4% of NSCLC

 

ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; HER: human epidermal growth factor receptor; NSCLC: non-small cell lung cancer; TK: tyrosine kinase; TKI: tyrosine kinase inhibitor.

Targeted Treatment Options

EGFR-Selective Small Molecule TKIs

Five orally administered EGFR-selective small-molecule TKIs have been approved by the U.S. Food and Drug Administration (FDA) for treating NSCLC: gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. Although the Food and Drug Administration (FDA) approved gefitinib in 2004, a phase three trial has suggested gefitinib was not associated with a survival benefit. In 2003, the FDA revised gefitinib labeling, further limiting its use to patients who had previously benefited or were currently benefiting from the drug; no new patients were to be given gefitinib. However, in 2015, the FDA approved gefitinib as a first-line treatment for patients with metastatic, sensitizing EGFR-variant positive NSCLC.

In 2015, osimertinib (Tagrisso; AstraZeneca), an irreversible selective EGFR inhibitor that targets T790M variant-positive NSCLC, received the FDA approval for patients with T890M-variant-positive NSCLC who have progressed on an EGFR TKI.

A meta-analysis by Lee et al (2013) assessing 23 trials on the use of erlotinib, gefitinib, and afatinib in patients with advanced NSCLC reported improved progression-free survival (PFS) in EGFR variant-positive patients treated with EGFR TKIs in the first- and second-line settings and as maintenance therapy. Comparators were chemotherapy, chemotherapy and placebo, and placebo in the first-line, second-line, and maintenance therapy settings. Among EGFR variant-negative patients, PFS was improved with EGFR TKIs compared with placebo for maintenance therapy but not in the first- and second-line settings. OS did not differ between treatment groups in either variant-positive or variant negative patients. Statistical heterogeneity was not reported for any outcomes. Reviewers concluded that EGFR-variant testing is indicated to guide treatment selection in NSCLC patients.

On the basis of the results of five phase three randomized controlled trials, the American Society of Clinical Oncology recommended 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 variants to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy.

The primary target population for TKIs in NSCLC is for EGFR variant-positive patients with advanced NSCLC. The use of TKIs in NSCLC for patients with non-sensitizing, wild-type EGFR-variant status is controversial. The TITAN trial (2012) demonstrated no significant differences in OS between erlotinib and chemotherapy as a second-line treatment for patients unselected on the basis of EGFR variant status, with fewer serious adverse events in erlotinib-treated patients. Karampeazis et al (2013) reported similar efficacy between erlotinib and standard chemotherapy (pemetrexed) for second-line therapy in patients unselected on the basis of EGFR variant status. By contrast, in the TAILOR trial (2013), standard chemotherapy was associated with longer OS than erlotinib for second-line therapy in patients with wild-type EGFR. Auliac et al (2014) compared sequential erlotinib plus docetaxel with docetaxel alone as second-line therapy among patients with advanced NSCLC and EGFR wild-type or unknown status. Based on a Simon’s optimal two-stage design, the erlotinib plus-docetaxel strategy was rejected. Despite the rejection, it is worth nothing that in the erlotinib plus docetaxel arm 18 of the 73 patients achieved PFS at 15 weeks; comparatively, in the docetaxel arm, 17 of 74 patients achieved PFS at 15 weeks.

Cicenas et al (2016) reported results of the IUNO randomized controlled trial, which compared maintenance therapy with erlotinib followed by second line chemotherapy if progression occurred to placebo followed by erlotinib if progression occurred in 643 patients with advanced NSCLC with no known EGFR variant. Because there were no significant differences between groups in terms of PFS, objective response rate, or disease control rate; maintenance therapy with erlotinib in patients without EGFR variants was not considered efficacious.

Exon 19 deletions and p.L858R point mutations in exon 21 are the most commonly described sensitizing EGFR mutations, or mutations in EGFR that are associated with responsiveness to EGFR TKI therapy. According to the NCCN, most recent data indicate that NSCLC tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI in any line of therapy.

Anti-EGFR Monoclonal Antibodies

For the treatment of KRAS-mutated NSCLC, anti-EGFR monoclonal antibodies have been investigated as possible treatment options. Available anti-EGFR monoclonal antibodies include cetuximab and panitumumab. The NCCN states that a combination of afatinib and cetuximab may be considered in patients harboring sensitizing EGFR mutations with disease progression on EGFR TKI therapy.

Programmed Death-Ligand 1 Inhibitors

Some tumors, including some NSCLCs, express a programmed death ligand 1 (PD-L1) on the cell surfaces to interact with host T-cells and evade the immune system. Several humanized monoclonal antibodies have been developed to act as immune checkpoint inhibitors by interfering with this interaction, to interact with the PD-L1, block the cancer/T-cell interaction, and thus act as immune checkpoint inhibitors. Pembrolizumab, nivolumab, and atezolizumab which inhibit the PD-1 receptor, and atezolizumab, which inhibits the PD-L1, are used in NSCLC which has PD-L1 expression on its cells. Durvalumab also targets the PD-L1 protein but is used in unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiotherapy.

Other Targeted Therapies

Crizotinib is a novel MET-, ROS-1-, and ALK-TKI, and associated with improved progression-free survival in patients with advanced NSCLC who are ALK gene rearrangement-positive. Crizotinib is considered first-line therapy for advanced ALK-positive lung adenocarcinoma. Other small molecule TKIs, designed to selectively bind to and inhibit ALK activation, have the FDA approval: ceritinib, alectinib, and brigatinib.

Proposed targeted therapies for other genetic alterations in NSCLC are trastuzumab for HER2 variants, crizotinib for MET amplification and ROS-1 rearrangement, vemurafenib and dabrafenib for BRAF variants and cabozantinib for RET rearrangements.

Proteomics Testing in Selecting Targeted Treatment for NSCLC

The term proteome refers to the entire complement of proteins produced by an organism, or cellular system and proteomics refers to the large-scale comprehensive study of a specific proteome. The proteome may differ from cell to cell and may vary over time and in response to selected stressors.

A cancer cell’s proteome is related to its genome and genomic alterations. The proteome may be measured by mass spectrometry (MS) or protein microarray. For cancer, proteomic signatures in the tumor or bodily fluids (i.e., pleural fluid or blood) other than the tumor have been investigated as a biomarker for cancer activity.

A commercially available serum-based test (VeriStrat) has been developed and proposed to be used as a prognostic tool to predict expected survival for standard therapies used in the treatment of NSCLC. The test is also proposed to have predictive value for response to EGFR TKIs. The test uses matrix-assisted laser desorption ionization MS analysis, and a classification algorithm was developed on a training set of pretreatment sera from three cohorts (Italian A, Japan A, Japan B) totaling 139 patients with advanced NSCLC who were treated with second-line gefitinib. The classification result is either “good” or “poor. Two validation studies using pretreatment sera from two cohorts of patients (Italian B, Eastern Cooperative Oncology Group 3503) totaling 163 patients have been reported.

This assay uses an eight-peak proteomic signature; four of the eight have been identified as fragments of serum amyloid A protein 1. This protein has been found to be elevated in individuals with a variety of conditions associated with acute and chronic inflammation. The specificity for malignant biologic processes and conditions has not been determined. With industry support, Fidler et al (2018) used convenience biorepository samples to investigate 102 analytes for potential correlations between the specific peptide and protein biomarkers and VeriStrat classification. The VeriStrat test is currently marketed as a tool to measure a patient's "immune response to lung cancer." Biodesix indicates that a VeriStrat "Good" result indicates "a disease state that is more likely to respond to standard of care treatment," whereas a VeriStrat "Poor" rating indicates a chronic inflammatory disease state associated with aggressive cancer and patients that "may benefit from an alternative treatment strategy." The Biodesix website does not indicate whether the VeriStrat test should be reserved for use in patients with advanced lung cancer.

Although the VeriStrat® matrix-assisted laser desorption ionization (MALDI)-MS-based predictive algorithm has the largest body of literature associated with it, other investigators have used alternative mass spectrometry methods, such as surface-enhanced laser desorption ionization/time-of-flight mass spectrometry, and alternative predictive algorithms, to assess proteomic predictors of lung cancer risk.

Best practices for peptide measurement and guidelines for publication of peptide and protein identification have been published for the research community.

Table. Targeted Treatment Options Approved by FDA

Drug

Indication

Manufacturer

Approved

NDA/BLA

Gefitinib (Iressa®)

Monotherapy for locally advanced or metastatic NSCLC after failure of platinum-based and docetaxel chemotherapies

Revised label to limit use to patients currently benefiting or previously benefited from gefitinib

First-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution variants as detected by an FDA-approved test

AstraZeneca

05/03

06/05

08/18

NDA 21-399

(Discontinued)

NDA 206995

NDA 206995/S3

Erlotinib (Tarceva®)

Monotherapy for treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen

Maintenance therapy for patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy

First-line treatment of patients with metastatic (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution variants as detected by an FDA-approved test

Treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution variants as detected by an FDA-approved test receiving first-line, maintenance, or second- or greater line treatment after progression following at least 1 prior chemotherapy regimen

OSI Pharmaceuticals and Genentech

11/04

04/10

05/13

10/16

NDA 021743

NDA 021743/S16

NDA 021743/S18

NDA 021743/S25

Afatinib (Gilotrif®)

First-line treatment of patients with metastatic (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution variants as detected by an FDA-approved test

Treatment of patients with metastatic, squamous, NSCLC progressing after platinum-based chemotherapy

Treatment of patients with NSCLC whose tumors have nonresistant EGFR variants as detected by an FDA-approved test, which includes additional variants other than EGFR exon 19 deletions or exon 21 (L858R) substitution variants

Boehringer Ingelheim

07/13

04/16

01/18

NDA 201292

NDA 201292/S7

NDA 201292/S14

Necitumumab (Portrazza®)

EGFR antagonist indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous NSCLC

Eli Lilly

11/15

BLA 125547

Osimertinib (Tagrisso®)

Treatment of patients with metastatic EGFR T790M variant-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy

First line treatment of patients with metastatic NSCLC whose tumors have, as detected by an FDA-approved test, EGFR exon 19 deletions or exon 21 L858R mutations

AstraZeneca

11/15

08/18

NDA 208065

NDA 208065/S11

Crizotinib (Xalkori®)

Treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test

Treatment of patients with metastatic NSCLC whose tumors are ROS1-positive

Treatment of patients with metastatic NSCLC whose tumors are ROS1- or ALK-positive

Novartis

08/11

03/16

NDA 202570

NDA 202570/S16

NDA 202570/S28

Ceritinib (Zykadia®)

A kinase inhibitor indicated for treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib

A kinase inhibitor indicated for treatment of patients with ALK-positive metastatic NSCLC

Novartis

04/14

NDA 205755 (Discontinued)

NDA 211225

Alectinib (Alecensa®)

A kinase inhibitor indicated for treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib

A kinase inhibitor indicated for treatment of patients with ALK-positive metastatic NSCLC as detected by an FDA-approved test

Hoffman-La Roche

12/15

06/18

NDA 208434

NDA 208434/S4

Brigatinib (Alunbrig®)

Treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib

ARIAD

04/17

NDA 208772

Pembrolizumab (Keytruda®)

Treatment of patients with metastatic, PD-L1- positive NSCLC, as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy

Treatment of patients with metastatic NSCLC whose tumors express PD-L1 [Tumor Proportion Score (TPS) ≥ 1%] as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy

Expansion of metastatic NSCLC indication to include first-line treatment of patients whose tumors have high PD-L1 expression (TPS ≥ 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations

Use in combination with pemetrexed and carboplatin, for the first-line treatment of patients with metastatic nonsquamous, NSCLC

Merck

10/15

10/16

10/16

05/17

BLA 125514/S5

BLA 125514/S8

BLA 125514/S12

BLA 125514/S16

Nivolumab (Opdivo®)

Treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving drug

Bristol-Myers Squibb

10/15

BLA 125554/S005

Atezolizumab (Tecentriq®)

Metastatic NSCLC patients who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Tecentriq.

Genentech

4/17

BLA 761034

Durvalumab (Imfinzi®)

Use in unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiotherapy

AstraZeneca

02/18

BLA 761069/S-002

Dacomitinib (Vizimpro®)

First-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations, as detected by an FDA-approved test

Pfizer

09/18

NDA 211288

Larotrectinib (Vitrakvi®)

A kinase inhibitor indicated for the treatment of patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment

Bayer

11/18

NDA 210861

Lorlatinib (Lorbrena®)

A kinase inhibitor indicated for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease, or alectinib as the first ALK inhibitor for metastatic disease, or ceritinib as the first ALK inhibitor for metastatic disease

Pfizer

11/18

NDA 210868

Dabrafenib (Tafinlar®)

A kinase inhibitor indicated for the treatment of patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test

Novartis

07/19

NDA 202806/S13

Trametinib (Mekinist®)

A kinase inhibitor indicated for the treatment of patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test

Novartis

07/19

NDA 204114/S13

Entrectinib (Rozlytrek®)

A kinase inhibitor for the treatment of patients with metastatic ROS1-positive NSCLC

Genentech

08/19

NDA 212726

ALK: anaplastic lymphoma kinase; BLA: biologics license application; EGFR: epidermal growth factor receptor; FDA: Food and Drug Administration; NDA: new drug application; NSCLC: non-small-cell lung cancer; PD-L1: programmed death-ligand 1; TKI: tyrosine kinase inhibitor; TPS: Tumor Proportion Score

KEY POINTS:

This evidence review has been updated regularly, with the most recent literature review occurred through August 20, 2020.

Summary of Evidence

For individuals with newly diagnosed NSCLC and wild-type EGFR variant status who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes retrospective studies and a prospective nonrandomized study. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. No published studies were identified that assessed the prognostic use of VeriStrat proteomic testing in newly diagnosed stage I or II NSCLC. For individuals with newly diagnosed advanced NSCLC and EGFR-negative variant status without prior systemic therapy, five studies have assessed the use of VeriStrat (“good” or “poor”) as a prognostic test to discriminate between overall survival (primary) progression-free survival (secondary) outcomes. All studies were retrospective and intended to validate the extent to which the VeriStrat proteomic classification correlated with overall survival or progression-free survival. Only one of the five studies reported the percentage of participants who were EGFR-negative, but it did not report outcomes based on variant status. One observational, nonrandomized study with prospective sample collection for proteomic testing before NSCLC treatment reported the percentage of participants who were EGFR-negative, but it did not report outcomes based on variant status. This was also the only study that included a first-line treatment consistent with current guideline-based recommendations¾platinum-doublet-based chemotherapy plus cisplatin or carboplatin plus pemetrexed. The VeriStrat classification was not used to direct the selection of treatment in any of the clinical trials from which the validation samples were derived. Disposition of populations with variant status “not reported” was generally not clear and could not be construed as “unknown” when wild-type or positive were reported. No studies were identified that used VeriStrat proteomic testing to inform therapeutic options for patients with stage I or II NSCLC if surgery or surgery plus radiotherapy have been completed or who were upstaged as a result of surgical findings. No studies were identified that used VeriStrat proteomic testing to inform therapeutic options for patients with stage I or II NSCLC who were considered medically inoperable. No studies were identified that used VeriStrat proteomic testing to predict response to first-line targeted therapies or first-line chemotherapy in patients with newly diagnosed advanced NSCLC. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with newly diagnosed NSCLC and unknown EGFR variant status who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes an RCT, four retrospective studies and a prospective study. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. All study populations were either unselected for EGFR-variant status or status was expressly reported as unknown in conjunction with negative or positive status reports. None of the studies that reported unknown EGFR-variant status reported outcomes for the proteomic score based on unknown EGFR-variant status. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with NSCLC and wild-type EGFR variant status and disease progression after first-line systemic therapy who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes an RCT. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. No studies were identified that reported or analyzed outcomes using the proteomic test as a prognostic tool in EGFR-negative variant status populations. The evidence includes an RCT (PROSE) using proteomic testing to predict response to erlotinib compared with chemotherapy as second-line treatment for patients with stage IIIB or IV NSCLC, stratified by performance status, smoking history, treatment center, and (masked) pretreatment VeriStrat classification. In a multivariable model to predict overall survival, which included clinical characteristics and EGFR-variant status, VeriStrat classification was significantly associated with overall survival (HR for VeriStrat “good” vs “poor,” 1.88; 95% CI, 1.25 to 2.84; p=0.003). However, 62% of the combined study population was EGFR-negative. A retrospective analysis was also performed on the MARQUEE trial, a phase III RCT in patients with stage IIIB or IV nonsquamous NSCLC, comparing patient response to erlotinib in conjunction with either tivantinib or a placebo; patients were stratified by EGFR/KRAS mutation status, gender, smoking history, and treatment history. Protocol treatments were subsequently discontinued by 93% of patients, and the trial was discontinued after prespecified interim futility analysis. In a multivariable model to predict overall survival, which included clinical characteristics and EGFR-variant status, VeriStrat classification was significantly associated with overall survival (hazard ratio for VeriStrat “good” vs “poor,” 0.52; 95% confidence interval, 0.40 to 0.67; p<0.001). 90% of the combined study population was EGFR-negative. An interaction between treatment and VeriStrat status was significant for multivariable analysis including EGFR status (p=0.036) but not significant for multivariable analysis including both EGFR and KRAS status (p=0.068). Currently, the use of erlotinib in patients unselected for the presence or absence of an EGFR-sensitizing variant is not standard clinical practice. It is recommended that variant status is determined, if not previously ascertained, before selecting treatment after progression or recurrence. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with NSCLC and unknown EGFR variant with disease progression after first-line systemic therapy who receive management with a serum proteomic test to predict survival and select treatment, the evidence includes three retrospective studies and two RCTs. The relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The use of VeriStrat as a prognostic test to discriminate between good and poor survival outcomes was assessed in three retrospective studies intended to validate the extent to which VeriStrat proteomic classification correlates with overall survival or progression-free survival. The VeriStrat classification was not used to direct treatment selection in any of the trials from which the validation samples were derived. None of the clinical trials from which the samples for VeriStrat proteomic classification were derived used a therapy consistent with current guidelines-based recommendations. The populations in all three studies were unselected for EGFR-variant status. In the PROSE RCT, using a multivariable model to predict overall survival, which included clinical characteristics and EGFR-variant status, VeriStrat classification was significantly associated with overall survival (HR for VeriStrat “good” vs “poor,” 1.88; 95% CI, 1.25 to 2.84; p=0.003). However, 32.6% of the combined study population had unknown EGFR status. In the EMPHASIS RCT, there were no significant differences in progression-free survival or overall survival among patients with VeriStrat “good” status receiving erlotinib or chemotherapy or among patients with VeriStrat “poor” status receiving erlotinib or chemotherapy. The results of the EMPHASIS RCT were restricted to squamous NSCLC histology. Currently, the use of erlotinib in patients unselected for the presence or absence of an EGFR-sensitizing variant is not standard clinical practice. It is recommended that variant status is determined, if not previously ascertained, before selecting treatment after progression or recurrence. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input from Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from one academic medical center and two community health systems, one of which provided four responses, while this policy was under review in 2017. Input was uniform that erlotinib is not considered routine for individuals with non-small-cell lung cancer (NSCLC) who are EGFR negative or EGFR status unknown in the second-line setting. Reviewers had limited confidence that there is adequate evidence that the use of VeriStrat® to guide treatment selection will improve outcomes for individuals with NSCLC who are EGFR negative or EGFR status unknown in the second-line setting.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

The NCCN (v8.2020) guidelines on the management of non-small cell lung cancer (NSCLC) recommend routine testing for EGFR variants in patients with advanced or metastatic non-squamous NSCLC (category 1 recommendation) and consideration for EGFR variant testing in patients with metastatic squamous NSCLC who were never smokers or with small biopsy specimens or mixed histology (category 2A recommendation). Recommendations for first-line treatment for EGFR-positive patients with advanced or metastatic NSCLC, and EGFR-negative or -unknown patients as well as for patients in either category who have progressed on therapy are provided.

American Society of Clinical Oncology

The American Society of Clinical Oncology (2017) updated its clinical practice guidelines on systemic therapy for stage IV NSCLC. New or revised recommendations included the following recommendations: first-line treatment for patients with nonsquamous cell carcinoma or squamous cell carcinoma (without positive markers, e.g., EGFR, ALK, ROS1), based on programmed death-ligand 1 expression; second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy based on programmed death-ligand 1 expression; as well as recommendations for those patients who cannot receive immune checkpoint inhibitor. Recommendations are included for patients with a sensitizing EGFR variant, for patients with disease progression after first-line EGFR tyrosine kinase inhibitor therapy based on the results of T790M variant testing, and for patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib, or if they previously received crizotinib, they may be offered chemotherapy.

The Society (2018) endorsed clinical practice guidelines from other medical associations (College of American Pathologists, International Association for the Study of Lung Cancer, Association for Molecular Pathology) addressing molecular testing for the selection of patient with lung cancer for treatment with targeted tyrosine kinase inhibitors.

American College of Chest Physicians

American College of Chest Physicians updated its evidence-based clinical practice guidelines on the treatment of Stage IV NSCLC in 2013. Based on a review of the literature, the American College of Chest Physicians reported improved response rates, progression-free survival, and toxicity profiles with first-line erlotinib or gefitinib compared with first-line platinum-based therapy in patients with EGFR variants, especially exon 19 deletion and L858R. Moreover, the American College of Chest Physicians recommended “testing patients with NSCLC for EGFR variants at the time of diagnosis whenever feasible, and treating with first-line EGFR-TKIs if mutation-positive.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Proteomic Testing, VeriStrat®, matrix assisted laser desorption ionization, MALDI, mass spectrometry, Non-small cell lung cancer, NSCLC

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The commercially available proteomic test (VeriStrat®; Biodesix) is available under the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

81538

Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival 

0080U

Oncology (lung), mass spectrometric analysis of galectin-3 binding protein and scavenger receptor cysteine-risch type 1 protein M130, with 5 clinical risk factors (age, smoking status, nodule diameter, nodule-spiculation status and nodule location), utilizing plasma, algorithm reported as a categorical probability of malignancy. (Effective 01/01/19)     

PREVIOUS CODING:

CPT codes:                 

84999

Unlisted chemistry procedure 

REFERENCES:

  1. Abbatiello S, Ackermann BL, Borchers C, et al. New guidelines for publication of manuscripts describing development and application of targeted mass spectrometry measurements of peptides and proteins. Mol Cell Proteomics. Mar 2017; 16(3):327-328.
  2. Akerley WL, Arnaud AM, Reddy B, et al. Impact of a multivariate serum-based proteomic test on physician treatment recommendations for advanced non-small-cell lung cancer. Curr Med Res Opin. Jun 2017; 33(6):1091-1097.
  3. Akerley WL, 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. Mar 2013; 79(3):307-311.
  4. 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. May 2013; 29(5):517-525.
  5. 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. Feb 2010; 5(2):169-178.
  6. Auliac JB, Chouaid C, Greillier L, et al. Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study. Lung Cancer. Sep 2014; 85(3):415-419.
  7. Biodesix. VeriStrat proteomic test. 2018; Available at: www.biodesix.com/veristrat/.
  8. Bozinovski S, Uddin M, Vlahos R, et al. Serum amyloid A opposes lipoxin A(4) to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A. Jan 17 2012; 109(3):935-940.
  9. Buttigliero C, Shepherd FA, Barlesi F, et al. Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer. Oncologist. Jun 2019; 24(6): e251-e259.
  10. 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. Nov 2012; 7(11):1653-1660.
  11. 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. Sep 2010; 69(3):337-340.
  12. Chansky K, Sculier JP, Crowley JJ, et al. The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol. Jul 2009; 4(7):792-801.
  13. Cicenas S, Geater SL, Petrov P, et al. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. Dec 2016; 102:30-37.
  14. Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. Mar 2012; 13(3):300-308.
  15. 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; Available at: www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.
  16. Diamandis EP. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst. Mar 3 2004; 96(5):353-356.
  17. Fidler MJ, Fhied CL, Roder J, et al. The serum-based VeriStrat(R) test is associated with proinflammatory reactants and clinical outcome in non-small cell lung cancer patients. BMC Cancer. Mar 20 2018; 18(1):310.
  18. Filippin-Monteiro FB, de Oliveira EM, Sandri S, et al. Serum amyloid A is a growth factor for 3T3-L1 adipocytes, inhibits differentiation and promotes insulin resistance. Int J Obes (Lond). Aug 2012; 36(8):1032-1039.
  19. Gadgeel S, Goss G, Soria JC, et al. Evaluation of the VeriStrat(R) serum protein test in patients with advanced squamous cell carcinoma of the lung treated with second-line afatinib or erlotinib in the phase III LUX-Lung 8 study. Lung Cancer. Jul 2017; 109:101-108.
  20. Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumors (TAILOR): a randomised controlled trial. The Lancet Oncology. 2013; 14(10):981-988.
  21. Gautschi O, Dingemans AM, Crowe S, et al. VeriStrat(R) has a prognostic value for patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab in the first line: pooled analysis of SAKK19/05 and NTR528. Lung Cancer. Jan 2013; 79(1):59-64.
  22. 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. Jun 2014; 15(7):713-7
  23. Grossi F, Genova C, Rijavec E, et al. Prognostic role of the VeriStrat test in first line patients with non-small cell lung cancer treated with platinum-based chemotherapy. Lung Cancer. Mar 2018; 117:64-69.
  24. Grossi F, Rijavec E, Genova C, et al. Serum proteomic test in advanced non-squamous non-small cell lung cancer treated in first line with standard chemotherapy. Br J Cancer. Jan 03 2017; 116(1):36-43.
  25. Hanna N, Johnson D, Temin S, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. Oct 20 2017; 35(30):3484-3515.
  26. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol. Apr 10 2005; 23(11):2544-2555.
  27. Hornberger J, Hirsch FR, Li Q, et al. Outcome and economic implications of proteomic test-guided second- or third-line treatment for advanced non-small cell lung cancer: extended analysis of the PROSE trial. Lung Cancer. May 2015; 88(2):223-230.
  28. 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. Aug 2008; 3(8):840-850.
  29. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted 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 Clinical Practice Guideline Update. J Clin Oncol. Mar 20 2018; 36(9):911-919.
  30. Karampeazis A, Voutsina A, Souglakos J, et al. Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. Cancer. Aug 1 2013; 119(15):2754-2764.
  31. 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. May 20 2011; 29(15):2121-2127.
  32. Keshtgarpour M, Tan WS, Zwanziger J, et al. Prognostic value of serum proteomic test and comorbidity index in diversified population with lung cancer. Anticancer Res. Apr 2016; 36(4):1759-1765.
  33. Kotani K, Koibuchi H, Yamada T, et al. The effects of lifestyle modification on a new oxidized low-density lipoprotein marker, serum amyloid A-LDL, in subjects with primary lipid disorder. Clin Chim Acta. Nov 2009; 409(1-2):67-69.
  34. 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. Nov 20 2012; 107(11):1820-1825.
  35. Lazzari C, Spreafico A, Bachi A, et al. Changes in plasma mass-spectral profile in course of treatment of non-small cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors. J Thorac Oncol. Jan 2012; 7(1):40-48.
  36. 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. May 1 2013; 105(9):595-605.
  37. Lee SM, Upadhyay S, Lewanski C et al. The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy. Eur. J. Cancer, 2019 Sep 10; 120:86-96.
  38. 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. Jul 2013; 8(7):823-859.
  39. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. Oct 20 2015; 33(30):3488-3515.
  40. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 3.2018. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
  41. 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. Dec 2013; 82(3):461-468.
  42. Peters S, Stahel RA, Dafni U, et al. Randomized phase III trial of erlotinib versus docetaxel in patients with advanced squamous cell non-small cell lung cancer failing first-line platinum-based doublet chemotherapy stratified by VeriStrat good versus VeriStrat poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial. J Thorac Oncol. Apr 2017; 12(4):752-762.
  43. Research OoCCP. What is Cancer Proteomics? //proteomics.cancer.gov/.
  44. 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. Jun 2009; 4(6):689-696.
  45. Santoso A, Kaniawati M, Bakri S, et al. Secretory phospholipase A2 Is associated with the odds of acute coronary syndromes through elevation of serum amyloid-A protein. Int J Angiol. Mar 2013; 22(1):49-54.
  46. Scagliotti G, von Pawel J, Novello S, et al. Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. Aug 20 2015; 33(24): 2667-74.
  47. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. Jun 20 2013; 368(25):2385-2394.
  48. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2005; 353(2):123-132.
  49. 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. May 2013; 143(5 Suppl):e341S-368S.
  50. 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. Apr 2013; 8(4):443-451.
  51. 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. Jul 9 2014:1-7.
  52. Surveillance Epidemiology and End Results Program. Cancer Stat Facts: Lung and Bronchus Cancer. n.d.; Available at: seer.cancer.gov/statfacts/html/lungb.html.
  53. 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. Jun 6 2007; 99(11):838-846.
  54. Wang DX, Liu H, Yan LR, et al. The relationship between serum amyloid A and apolipoprotein A-I in high-density lipoprotein isolated from patients with coronary heart disease. Chin Med J (Engl). Oct 2013; 126(19):3656-3661.
  55. Wheatley-Price P, Blackhall F, Lee SM, et al. The influence of sex and histology on outcomes in non-small-cell lung cancer: a pooled analysis of five randomized trials. Ann Oncol. Oct 2010; 21(10):2023-2028.
  56. 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.
  57. Yang L, Tang C, Xu B, et al. Classification of epidermal growth factor receptor gene mutation status using serum proteomic profiling predicts tumor response in patients with stage IIIB or IV non-small-cell lung cancer. PLoS One. 2015; 10(6):e0128970.

POLICY HISTORY:

Medical Policy Panel, October 2014

Medical Policy Group, October 2014 (1): New policy, previously only listed on the Investigational Listing; remains investigational

Medical Policy Administration Committee, November 2014

Available for comment October 24 through December 7, 2014

Medical Policy Panel, October 2015

Medical Policy Group, October 2015 (3):  2015 Updates to Description, Key Points, Governing Bodies, Coding & References; no change in policy statement

Medical Policy Group, November 2015: 2016 Annual Coding Update. Created previous coding section and moved CPT 84999 to this section.

Medical Policy Group, December 2015 (4): 2016 Update to Key Points; update to literature review search date.

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points, and References; no change to policy statement.

Medical Policy Panel, November 2017

Medical Policy Group, November 2017 (3): 2017 Updates to Description, Key Points, and References; no change to Policy statement.

Medical Policy Panel, April 2018

Medical Policy Group, May 2018 (2): 2018 Updates to Title, Description, Key Points, Key Words, and References; no change to Policy Statement.

Medical Policy Panel, November 2018

Medical Policy Group, November 2018 (9): 2018 Updates to Description and Key Points.  No change to policy statement.

Medical Policy Group, December 2018: 2019 Coding updated.  Added new CPT code 0080U to Current Coding.

Medical Policy Panel, November 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, November 2020

Medical Policy Group, November 2020 (9): 2020 Updates to Key Points, References. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.