Thursday, January 10, 2019

CPT 81538 - Proteomic Testing for Targeted Therapy in Non-Small Cell Lung Cancer

Coding Code DescriptionCPT

81538 Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival

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


Genes in our DNA tell a cell how to make proteins. The study of proteins in a cell is called “proteomics.” Doing tests on the proteins in a cell (“proteomic testing”) may help to identify which drugs might be helpful in treating non-small cell lung cancer and how aggressive the cancer is. Proteomic testing used for this and all other reasons is unproven (investigational). Medical studies have not determined the types of patients in which proteomic testing could predict the course of the disease. Studies also have not shown that patients whose treatments were chosen based on proteomic testing survived longer than those whose treatments were selected without proteomic testing.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria

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

Related Information N/A Evidence Review Description

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).

Background Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200new cases and 158,040 deaths due to the disease in 2015.1 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.


The stage at which lung cancer is diagnosed has the greatest impact on prognosis.2 Localized disease confined to the primary site has a 55.6% relative 5-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, accounts 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 advanced disease and up to 40% of 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 2349 advanced NSCLC patients from 5 randomized chemotherapy trials.3 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.4

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


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). The clinical management pathway for stage I or II NSCLC is\ shown in Figure

The clinical management pathway for newly diagnosed advanced NSCLC is shown in Figure 2.1 Treatment recommendations are based on the overall health or performance status of the patient as well as the presence or absence of a treatment-sensitizing genetic variant. The latter is  used to select for targeted therapy or platinum-based chemotherapy.The clinical management pathway for advanced NSCLC after progression on first-line treatment or recurrence is shown in Figure 3. Treatment options are based on objective response to prior therapy, duration of response, as well as the type of and duration of prior therapy (either targeted therapy or chemotherapy).

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 tyrosine kinase receptor (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, 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. Variants 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 variants in NSCLC varies by population, with the highest prevalence in nonsmoking, Asian women with adenocarcinoma; for that subpopulation EGFR variants have been reported as high as 30% to 50%. The reported prevalence of EGFR variants in lung adenocarcinoma patients in the United States is approximately 15%.5

ALK Variants

In 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 (EML4) gene and the ALK gene (EML4-ALK), which is created by an inversion on chromosome 2p.6 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 Table 1.

The role of testing for these variants to help select targeted therapies for NSCLC is less wellestablished than for EGFR variants

Non-EGFR Mutations in NSCLC Gene Gene Function Estimated Mutation Prevalence in NSCLC Patient and Tumor Characteristics KRAS Encodes RAS proteins; variants associated with constitutively activated protein
20%-30% Adenocarcinomas Heavy smokers ROS1 Encodes a receptor TK in the insulin receptor family
0.9%-3.7% Adenocarcinoma Never smokers RET Proto-oncogene that encodes a receptor TK growth factor
0.6%-2% MET Oncogene that encodes a receptor TK 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

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

Three orally administered EGFR-selective small molecule TKIs have been identified for treating NSCLC: gefitinib (Iressa), erlotinib (Tarceva®), and afatinib (Gilotrif™). Although the Food and Drug Administration (FDA) approved gefitinib in 2004, a phase 3 trial 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 benefitted or were currently benefiting from the drug; no new patients were to be given gefitinib. However, in 2015, the FDA approved gefitinib as firstline treatment for patients with metastatic NSCLC for patients with EGFR-mutated tumors. Erlotinib and afatinib also have approval by the FDA.

In 2015, osimertinib (Tagrisso), an irreversible selective EGFR inhibitor that targets T790M variant-positive NSCLC, received FDA approval for patients with T790M-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.7 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. Overall survival (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 mutation testing is indicated to guide treatment selection in NSCLC patients.

On the basis of the results of 5 phase 3 randomized controlled trials, the American Society of  Clinical Oncology recommended that patients with NSCLC being considered for first-linetherapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR 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 in EGFR variant*negative patients is controversial. The TITAN trial as reported by Ciuleanu et al (2012) demonstrated no significant differences in OS between erlotinib and chemotherapy as second-line treatment for patients unselected on the basis of EGFR mutation status, with fewer serious adverse events in erlotinib-treated patients.8 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 mutation status.9 By contrast, in the TAILOR trial as reported by Garassino et al (2013), standard chemotherapy was associated with longer OS than erlotinib for second-line therapy in patients with wild-type EGFR.10 Auliac et al (2014) compared sequential erlotinib plus docetaxel with docetaxel alone as second-line therapy among patients with advanced NSCLC and EGFR wildtype or unknown status.11 Based on Simon’s optimal 2-stage design, the erlotinib plus docetaxel strategy was rejected. Despite the rejection, it is worth noting that in the erlotinib plus docetaxel arm 18 of 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 using erlotinib followed by second-line chemotherapy if progression occurred to placebo followed by erlotinib if progression occurred in 643 patients who had advanced NSCLC and no known EGFR variant.12 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.

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. Neither drug has an established role in the treatment of NSCLC either as a component of initial therapy or as second-line 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 interferingwith 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 programmed death 1 receptor, and atezolizumab, which inhibits the PD-L1, are used in NSCLC that have 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, ROS1, and ALK TKI, and associated with improved PFS in patients with advanced NSCLC who are ALK gene rearrangement*positive.13 Crizotinib is considered first-line therapy for advanced ALK-positive lung adenocarcinoma.1 Other small molecule TKIs, designed to selectively bind to and inhibit ALK activation, have 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 ROS1 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 to genomic alterations. The proteome may be measured by mass spectrometry (MS) 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. 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.14

The test uses matrix-assisted laser desorption ionization MS analysis, and a classification algorithm was developed on a training set of pretreatment sera from 3 cohorts (Italian A, Japan A, Japan B) totaling 139 patients with advanced NSCLC who were treated with second-line gefitinib.15 The classification result is either “good” or “poor. Two validation studies using pretreatment sera from 2 cohorts of patients (Italian B, Eastern Cooperative Oncology Group 3503) totaling 163 patients have been reported.

This assay uses an 8-peak proteomic signature; 4 of the 8 have been identified as fragments of serum amyloid A protein 1.16 This protein has been found to be elevated in individuals with a variety of conditions associated with acute and chronic inflammation.17-21 The specificity for malignant biologic processes and conditions has not been determined.22 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.23

Although the VeriStrat matrix-assisted laser desorption ionization 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 MS, and alternative predictive algorithms, to assess proteomic predictors of lung cancer risk.24 Best practices for peptide measurement and guidelines for publication of peptide and protein identification have been published for the research community.

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