Latest Review Date: June 2024

Category: Laboratory

POLICY:

Plasma-based proteomic screening, including but not limited to Nodify XL2® (BDX-XL2), Nodify CDT®, and REVEAL Lung Nodule Characterization (MagArray), in individuals with undiagnosed pulmonary nodules detected by computed tomography is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Plasma-based proteomic screening is a type of molecular testing available in the diagnostic workup of pulmonary nodules. To rule out malignancy, invasive diagnostic procedures such as computed tomography-guided biopsies, bronchoscopies, or video-assisted thoracoscopic procedures are often required, but each carry procedure-related complications ranging from post procedure pain to pneumothorax. This type of diagnostic testing has been proposed for use as an aid in risk-stratifying patients to eliminate or necessitate the need for subsequent invasive diagnostic procedures.

Pulmonary Nodules

Pulmonary nodules are a common clinical problem that may be found incidentally on a chest x-ray or computed tomography (CT) scan or during lung cancer screening studies of smokers. The primary question after the detection of a pulmonary nodule is the probability of malignancy, with subsequent management of the nodule based on various factors such as the radiographic characteristics of the nodules (e.g., size, shape, density) and patient factors (e.g., age, smoking history, previous cancer history, family history, environmental/occupational exposures). The key challenge in the diagnostic workup for pulmonary nodules is appropriately ruling in patients for invasive diagnostic procedures and ruling out patients who should forgo invasive diagnostic procedures. However, due to the low positive predictive value of pulmonary nodules detected radiographically, many unnecessary invasive diagnostic procedures and/or surgeries are performed to confirm or eliminate the diagnosis of lung cancer.

Proteomics

Proteomics is the study of the structure and function of proteins. The study of the concentration, structure, and other characteristics of proteins in various bodily tissues, fluids, and other materials has been proposed as a method to identify and manage various diseases, including cancer. In proteomics, multiple test methods are used to study proteins. Immunoassays use antibodies to detect the concentration and/or structure of proteins. Mass spectrometry is an analytic technique that ionizes proteins into smaller fragments and determines mass and composition to identify and characterize them.

Plasma-Based Proteomic Screening for Pulmonary Nodules

Plasma-based proteomic screening has been investigated to risk-stratify pulmonary nodules as likely benign to increase the number of patients who undergo serial CT scans of their nodules (active surveillance), instead of invasive procedures such as CT-guided biopsy or surgery. Additionally, proteomic testing may also determine a likely malignancy in clinically low-risk or intermediate-risk pulmonary nodules, thereby permitting earlier detection in a subset of patients.

Nodify XL2 (BDX-XL2) is a plasma-based proteomic screening test that measures the relative abundance of proteins from multiple disease pathways associated with lung cancer using an analytic technique called multiple reaction monitoring mass spectroscopy. The test helps physicians identify lung nodules that are likely benign or at lower risk of cancer. If the test yields a "likely benign" or "reduced risk" result, patients may choose active surveillance via serial CT scans to monitor the pulmonary nodule. Earlier generations of the Nodify XL2 test include Xpresys Lung® and Xpresys Lung 2®.

Nodify CDT® is a proteomic test that uses multi-analyte immunoassay technology to measure autoantibodies associated with tumor antigens. The test helps physicians identify lung nodules that are likely malignant or at higher risk of cancer. Patients with a "high level" Nodify CDT test result have a higher risk of malignancy than predicted by clinical factors alone; invasive diagnostic procedures would be indicated in these cases.

The Nodify XL2 and Nodify CDT tests are therefore only used in the management of pulmonary nodules to rule out or rule in, invasive diagnostic procedures; they do not diagnose lung cancer. These tests are offered together as Biodesix’s Nodify Lung® testing strategy, but physicians may also choose to order each test independently.

REVEAL Lung Nodule Characterization (MagArray) is a plasma-protein biomarker test that may aid clinicians in characterizing indeterminate pulmonary nodules (4 to 30 mm) in current smokers 25 years of age and older. The test is based on a multianalyte assay with a proprietary algorithmic analysis using immunoassay, microarray, and magnetic nanoparticle detection techniques to obtain laboratory data for calculation of the risk score for lung cancer. The REVEAL Lung Nodule Characterization is presented on a scale from 0 to 100 with a single cut point at 50. The score is based on the measurement of 3 clinical factors (age, sex, and nodule diameter) and 3 proteins (epidermal growth factor receptor, prosurfactant protein B, and tissue inhibitor of metalloproteinases 1) associated with the presence of lung cancer. It may aid a clinician in the decision to perform a biopsy or to consider routine monitoring. It is not intended as a screening or stand-alone diagnostic assay.

KEY POINTS:

The most recent literature update was performed through March 27, 2024.

Summary of Evidence

For individuals with undiagnosed pulmonary nodules detected by computed tomography who receive plasma-based proteomic screening, the evidence includes prospective cohorts, retrospective studies, and prospective-retrospective studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, hospitalizations, and resource utilization. Clinical validation studies were identified for 2 versions (Xpresys Lung, and Xpresys Lung version 2 [now Nodify XL2]) of a proteomic classifier and another lung nodule characterization test (REVEAL). The Nodify XL2 classifier has undergone substantial evolution, from a 13-protein assay to a 2-protein assay integrated with clinical factors. Because of this evolution, the most relevant studies are with the most recent version 2 (Xpresys Lung version 2 [now Nodify XL2]). One validation study on version 2 has been identified. The classifier has been designed to have high specificity for malignant pulmonary nodules, and the validation study showed a specificity of 97% for patients with a low-to-moderate pretest probability (≤50%) of a malignant pulmonary nodule. The primary limitation of this study is that a high number of patients were excluded from the study due to incomplete clinical data or because they were subsequently determined to be outside of the intended use population. It is unclear if the intended use population was determined a priori. Validation in an independent sample in the intended use population is needed. No recent clinical validation studies were identified for the Nodify CDT test or the Nodify Lung testing strategy. The REVEAL validation study was a retrospective study that demonstrated use as a rule-out test in conjunction with the Veteran's Affairs (VA) Clinical Factors Model when the samples were considered inconclusive or intermediate risk by the VA model. The REVEAL model subsequently correctly identified 65% intermediate-risk samples as either low or high risk. The negative predictive value and sensitivity were both 94%. Limitations included a small sample size and use in conjunction with just 1 type of testing model. Validation in an independent sample in the intended use population with additional probability models is needed. Indirect evidence suggests that a proteomic classifier with a high negative predictive value has the potential to reduce the number of unnecessary invasive procedures to definitively diagnose benign disease versus malignancy. However, long-term follow-up data would be required to determine the survival outcomes in patients with a missed diagnosis of lung cancer at earlier, more treatable stages. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

American College of Chest Physicians

In 2013, the American College of Chest Physicians published evidence-based clinical practice guidelines on the diagnosis and management of lung cancer, including pulmonary nodules.

The relevant population of interest is individuals with undiagnosed pulmonary nodules. In particular, as outlined in the evidence-based American College of Chest Physicians guidelines (2013) on the diagnosis and management of lung cancer, decision-making about a single indeterminate lung nodule eight to 30 mm in diameter on a CT scan is complicated, requiring input about the patient's pretest probability of lung cancer, the characteristics of the lung nodule on CT, and shared decision-making between the patient and physician about follow-up. Therefore, additional information in the segment of patients with an indeterminate lung nodule, eight to 30 mm in diameter, would be particularly useful.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer, small cell lung cancer, or lung cancer screening do not mention plasma-based proteomic screening testing or gene expression profiling as a potential diagnostic or screening tool.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Xpresys Lung, Xpresys Lung 2, BDX-XL2, Biodesix, Integrated Diagnostics, Proteomics, Pulmonary Nodules, Nodify XL2, Nodify CDT® , REVEAL Lung Nodule Characterization, MagArray

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 (CLIA). Xpresys Lung 2, now Nodify XL2 (BDX-XL2; Integrated Diagnostics [Indi], purchased by Biodesix); Nodify CDT (Biodesix); REVEAL Lung Nodule Characterization (MagArray); and Percepta Genomic Sequencing Classifier (Veracyte) are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) 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.

CURRENT CODING:

CPT Codes:

REFERENCES:

1. Biodesix. Nodify Lung: Lung Nodule Management. 2024; www.biodesix.com/our-tests/nodify-lung.
2. Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. May 2013; 143(5 Suppl): 7S-37S.
3. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it 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): e93S-e120S.
4. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
5. Kearney P, Hunsucker SW, Li XJ, et al. An integrated risk predictor for pulmonary nodules. PLoS One. 2017; 12(5):e0177635.
6. Kuang, MM, Tao, XX, Peng, YY, Zhang, WW, Pan, YY, Cheng, LL, Yuan, CC, Zhao, YY, Mao, HH, Zhuge, LL, Zhou, ZZ, Chen, HH, Sun, YY. Proteomic analysis of plasma exosomes to differentiate malignant from benign pulmonary nodules. Clin Proteomics, 2019 Feb 9; 16:5.
7. Li XJ, Hayward C, Fong PY, et al. A blood-based proteomic classifier for the molecular characterization of pulmonary nodules. Sci Transl Med. Oct 16 2013; 5(207):207ra142.
8. Li XJ, Lee LW, Hayward C, et al. An integrated quantification method to increase the precision, robustness, and resolution of protein measurement in human plasma samples. Clin Proteomics. 2015; 12(1):3.
9. Martínez-Terroba, EE, Behrens, CC, de Miguel, FF, Agorreta, JJ, Monsó, EE, Millares, LL, Sainz, CC, Mesa-Guzman, MM, Pérez-Gracia, JJ, Lozano, MM, Zulueta, JJ, Pio, RR, Wistuba, II, Montuenga, LL, Pajares, MM. A novel protein-based prognostic signature improves risk stratification to guide clinical management in early-stage lung adenocarcinoma patients. J. Pathol., 2018 May 15; 245(4).
10. Mazzone P, Dotson T, Wahidi MM, et al. Clinical validation and utility of Percepta GSC for the evaluation of lung cancer. PLoS One. 2022; 17(7): e0268567.
11. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2024: Small Cell Lung Cancer. 2023; www.nccn.org/professionals/physician_gls/pdf/sclc.pdf.
12. National Comprehensive Cancer Network. NCCN Guidelines Version 3.2024: Non-Small Cell Lung Cancer. 2024; www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
13. Pritchett MA, Sigal B, Bowling MR, et al. Assessing a biomarker's ability to reduce invasive procedures in patients with benign lung nodules: Results from the ORACLE study. PLoS One. 2023; 18(7): e0287409.
14. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of 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): e142Se165S.
15. Silvestri GA, Tanner NT, Kearney P, et al. Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial. Chest. Sep 2018; 154(3): 491-500.
16. Tanner NT, Springmeyer SC, Porter A, et al. Assessment of Integrated Classifier's Ability to Distinguish Benign From Malignant Lung Nodules: Extended Analyses and 2-Year Follow-Up Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial. Chest. Mar 2021; 159(3): 1283-1287.
17. Vachani A, Hammoud Z, Springmeyer S, et al. Clinical utility of a plasma protein classifier for indeterminate lung nodules. Lung. Dec 2015; 193(6):1023-1027.
18. Vachani A, Pass HI, Rom Wn, et al. Validation of a multiprotein plasma classifier to identify benign lung nodules. Supplement. J Thorac Oncol. April 2015; 10(4):629-637. cdn-links.lww.com/permalink/jto/a/jto_10_4_2015_01_07_massion_jto-d-14-00912_sdc1.pdf. 

POLICY HISTORY:

Medical Policy Group, February 2020 (9): Individual policy created with full literature review for plasma proteomic screening of pulmonary nodules. Pulling previous applicable information from medical policy #644. No change to policy statement – still considered investigational.

Medical Policy Panel, May 2020

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

Medical Policy Panel, June 2021

Medical Policy Group, December 2021 (9): 2021 Updates to Key Points, Description, References. Policy statement updated to remove “not medically necessary,” and replace Xpresys® Lung and Xpresys® Lung 2 with BDX-XL2 (Nodify XL2). Integrated Diagnostics [Indi], the manufacturer of Xpresys products was purchased by Biodesix, the manufacturer of Nodify products. No change to policy intent. Key Word added: Nodify

Medical Policy Panel, May 2022

Medical Policy Group, May 2022 (9): 2022 Updates to Key Points, Description, References. Replaced the word “patients” with “individuals” in policy statement, no change to intent of coverage.

Medical Policy Panel, May 2023

Medical Policy Group, May 2023 (5): Updates to Description, Key Points, Key Words, Approved by Governing Bodies, Benefit Application, and References. No change to Policy Statement.

Medical Policy Group, July 2023 (5): 2023 Annual Coding Update: Added CPT code 0360U to Current Coding Section. No change to Policy Statement.

Medical Policy Panel, May 2024

Medical Policy Group, June 2024 (5): Updates to Description, Key Points, Key Words: REVEAL Lung Nodule Characterization, and MagArray. Updates to Approved by Governing Bodies. Updates to Current Coding section to include CPT code 0092U, and References. Policy Statement updated to include Nodify CDT® and REVEAL Lung Nodule Characterization (MagArray) as additional investigational labs. These labs were previously considered investigational. No change to Policy intent.

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.