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

POLICY NUMBER

A.2.04.125

DESCRIPTION

Proteomic testing has been proposed as a way to predictsurvival 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.

Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death in the United States, with an estimated 234,580 new cases and 125,070 deaths due to the disease in 2024. Non-small-cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases and includes nonsquamous carcinoma (adenocarcinoma, large cell carcinoma, and 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 59.8% relative 5-year survival but accounts for only 18% of lung cancer cases at diagnosis. Mortality increases sharply with advancing stage. Metastatic lung cancer has a relative 5-year survival of 6.3%. 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 and colleagues reported on a retrospective pooled analysis of 2,349 advanced NSCLC patients from 5 randomized chemotherapy trials. Women had a higher response rate to platinum-based chemotherapy than men. Additionally, women with adenocarcinoma histology had greater overall survival than men. 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 the 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 (eg, 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. The NCCN also includes recommendations for targeted therapy or immunotherapy in patients with biomarkers, including sensitizing epidermal growth factor receptor (EGFR) mutations. 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, erlotinib plus ramucirumab, erlotinib plus bevacizumab (nonsquamous), 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. 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 tyrosine kinase (TK) receptor, 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 the stimulation of neovascularization.

Variants in two 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%.

ALK Variants

For 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 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

There are other genetic variants identified in subsets of patients with NSCLC. The role of testing for these variants is to help select targeted therapies for NSCLC (see the Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS)  medical policy).

Targeted Treatment Options

EGFR-Selective Small Molecule Tyrosine Kinase Inhibitors

Orally administered EGFR-selective small-molecule TKIs approved by the U.S. Food and Drug Administration (FDA) for treating NSCLC include: gefitinib, erlotinib, afatinib, dacomitinib, mobocertinib, and osimertinib. Although the FDA approved gefitinib in 2004, a phase 3 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 benefitted 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), an irreversible selective EGFR inhibitor that targets T790M variant-positive NSCLC, received the FDA approval for patients with T790Mvariant-positive NSCLC who have progressed on an EGFR TKI.

A 2013 meta-analysis of 23 trials assessing 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. 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-variant 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 in 2011 that patients with NSCLC 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 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 demonstrated no significant differences in overall survival between erlotinib and chemotherapy as second-line treatment for patients unselected on the basis of EGFR-variant status, with fewer serious adverse events in erlotinib-treated patients. Karampeazis and colleagues 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, standard chemotherapy was associated with longer overall survival than erlotinib for second-line therapy in patients with wild-type EGFR. Auliac and colleagues 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 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 the 73 patients achieved PFS at 15 weeks; comparatively, in the docetaxel arm, 17 of 74 patients achieved PFS at 15 weeks.

In 2016, Cicenas and colleagues reported results of the IUNO randomized controlled trial, which compared maintenance therapy using erlotinib followed by second-line chemotherapy if progression occurred with placebo followed by erlotinib if progression occurred in 643 patients who had advanced NSCLC and no known EGFR variant. Because there were no significant differences between groups in 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.

Proteomics Testing for Selecting Targeted Treatment for Non-Small Cell Lung Cancer

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 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. 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. 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 and colleagues 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."

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 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.

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

Related medical policies –

• Multimarker Serum Testing Related to Ovarian Cancer

• Molecular Analysis for Targeted Therapy or Immunotherapy of Non-Small-Cell Lung Cancer

POLICY

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.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

04/09/2015: Approved by Medical Policy Advisory Committee.

08/14/2015: Code Reference section updated for ICD-10.

01/05/2016: Policy description updated regarding EGFR-selective small molecule tyrosine kinase inhibitors. Policy statement unchanged.

01/08/2016: Code Reference section updated to add new 2016 CPT code 81538.

06/07/2016: Policy number A.2.04.125 added.

02/24/2017: Policy description updated regarding non-EGFR variants and targeted treatment options. Policy statement unchanged.

01/09/2018: Policy description updated. Policy statement unchanged.

05/01/2018: Policy title changed from "Proteomic Testing for Targeted Therapy in Non-Small-Cell Lung Cancer" to "Proteomic Testing for Systemic Therapy in Non-Small-Cell Lung Cancer." Policy description updated regarding the impact the stage of diagnosis has on prognosis. Added information regarding the VeriStrat test. Policy statement unchanged.

01/09/2019: Policy description updated regarding treatment options for non-small-cell lung cancer. Policy statement unchanged.

07/01/2019: Code Reference section updated to add new CPT code 0092U.

12/11/2019: Policy description updated to remove information regarding clinical management pathways for NSCLC and to add information regarding treatment. Policy statement unchanged.

01/15/2021: Policy description updated. Policy statement unchanged.

02/03/2022: Policy description updated regarding estimated cases of NSCLC and treatment. Policy statement unchanged.

02/08/2023: Policy title changed from "Proteomic Testing for Systemic Therapy in Non-Small-Cell Lung Cancer" to "Proteomic Testing for Targeted Therapy in Non-Small-Cell Lung Cancer." Policy description updated. Policy statement unchanged.

01/04/2024: Policy description updated. Policy statement unchanged.

01/29/2025: Policy description updated regarding new data for lung cancer. Policy statement unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.125

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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