Molecular Testing in the Management of Pulmonary Nodules Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 11|01|2025 POLICY LAST REVIEWED: 07|02|2025 OVERVIEW Plasma-based proteomic screening and gene expression profiling of bronchial brushing are molecular tests available in the diagnostic workup of pulmonary nodules. To rule out malignancy, invasive diagnostic procedures such as computed tomography (CT) guided biopsies, bronchoscopies, or video assisted thoracoscopic are often required, but each carry procedure-related complications ranging from post procedure pain to pneumothorax. Molecular diagnostic tests have been proposed to aid in risk stratifying patients to eliminate or necessitate the need for subsequent invasive diagnostic procedures. The following tests are addressed in this policy: • Nodify CDT® (Biodesix®, Inc) (CPT code 0360U) • REVEAL Lung Nodule Characterization (MagArray) (CPT code 0092U) MEDICAL CRITERIA Medicare Advantage Plans and Commercial Products Effective 11/1/2025, the following test(s) are considered medically necessary when the medical criteria in the online authorization tool for participating providers is met:
• Nodify XL2 (BDX-XL2) (Biodesix®, Inc) - CPT code 0080U • Percepta® Bronchial Genomic Classifier (Veracyte) - CPT code 81479 PRIOR AUTHORIZATION
Medicare Advantage Plans and Commercial Products Prior Authorization is required for the Percepta® Bronchial Genomic Classifier (Veracyte) test and Nodify XL2 (BDX-XL2) test for Medicare Advantage Plans and is recommended for Commercial Products.
There is no specific CPT coding for some of the services referenced in this policy. Therefore, an Unlisted CPT code should be used (see Coding Section for details). All Unlisted genetic testing CPT codes require prior authorization to determine what service is being rendered and if the service is covered or not medically necessary. See the Related Policies section.
Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.
In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member. Medical Coverage Policy | Molecular Testing in the Management of Pulmonary Nodules

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

POLICY STATEMENT Medicare Advantage Plans and Commercial Products The following test(s) are covered: • Nodify CDT® is covered.

Effective 11/1/2025, the following test(s) may be considered medically necessary when the medical criteria in the online authorization tool for participating providers is met:
• Nodify XL2 (BDX-XL2) (Biodesix®, Inc) • Percepta® Bronchial Genomic Classifier (Veracyte)

The following test(s) are not covered for Medicare Advantage Plans and not medically necessary for Commercial Products as evidence is insufficient to determine that the technology results in an improvement in the net health outcome:
• REVEAL Lung Nodule Characterization (MagArray)

Commercial Products
Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information.

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate section of the Benefit Booklet, Evidence of Coverage or Subscriber Agreement for services not covered/medically necessary.

BACKGROUND 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

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

a likely malignancy in clinically low-risk or intermediate-risk pulmonary nodules, thereby permitting earlier detection in a subset of patients.

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.

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.

Gene Expression Profiling Gene expression profiling (GEP) is the measurement of the activity of genes within cells. Messenger RNA serves as the bridge between DNA and functional proteins. Multiple molecular techniques such as Northern blots, ribonuclease protection assay, in situ hybridization, spotted complementary DNA arrays, oligonucleotide arrays, reverse transcriptase polymerase chain reaction, and transcriptome sequencing are used in GEP. An important role of GEP in molecular diagnostics is to detect cancer-associated gene expression of clinical samples to assess for the risk for malignancy.

Regulatory Status 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). Nodify CDT (Biodesix); and REVEAL Lung Nodule Characterization (MagArray); 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 this test.

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. 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% of 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 inpatients 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.

CODING The following code(s) are covered for Medicare Advantage Plans and Commercial Products:

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

Nodify CDT®
0360U Oncology (lung), enzyme-linked immunosorbent assay (ELISA) of 7 autoantibodies (p53, NY-ESO- 1, CAGE, GBU4-5, SOX2, MAGE A4, and HuD), plasma, algorithm reported as a categorical result for risk of malignancy (Nodify CDT® Biodesix, Inc.)

Effective 11/1/2025, the following CPT code(s) may be considered medically necessary for Medicare Advantage Plans and Commercial Products when the medical criteria in the online authorization tool for participating providers is met: • Nodify XL2 (BDX-XL2) – CPT Code 0080U • Percepta® Bronchial Genomic Classifier – CPT Code 81479

The following code(s) are not covered for Medicare Advantage Plans and are not medically necessary for Commercial Products:

REVEAL Lung Nodule Characterization 0092U Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor

         technology, plasma, algorithm reported as risk score for likelihood of malignancy (REVEAL  
         Lung Nodule Characterization)

RELATED POLICIES Biomarker Testing Mandate
Centers for Medicare and Medicaid Services (CMS) National and Local Coverage Determinations Genetic Testing Services Proprietary Laboratory Analysis (PLA) Unlisted Procedures

PUBLISHED Provider Update, January/September 2025 Provider Update, April 2024 Provider Update, November 2023 Provider Update, October 2022 Provider Update, October 2021, February 2021

REFERENCES:

1. Centers for Medicare and Medicaid Services (CMS) Local Coverage Determination (LCD) L35160, MolDX: Molecular Diagnostic Tests (MDT)
2. Centers for Medicare and Medicaid Services (CMS) Local Coverage Determination (LCD) article, A59641, Article - Billing and Coding: MolDX: Proteomics Testing
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. PMID23649456
4. 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. PMID 24132637
5. Vachani A, Pass HI, Rom WN, et al. Validation of a multiprotein plasma classifier to identify benign lungnodules. J Thorac Oncol. Apr 2015; 10(4): 629-37. PMID 25590604
6. Vachani A, Hammoud Z, Springmeyer S, et al. Clinical Utility of a Plasma Protein Classifier for Indeterminate Lung Nodules. Lung. Dec 2015; 193(6): 1023-7. PMID 26376647
7. Kearney P, Hunsucker SW, Li XJ, et al. An integrated risk predictor for pulmonary nodules. PLoS One.2017; 12(5): e0177635. PMID 28545097
8. 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. PMID 29496499

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

9. 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. PMID 33171158
10. 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. https://cdn- links.lww.com/permalink/jto/a/jto10420150107massionjto-d-14-00912sdc1.pdf.
11. Trivedi NN, Arjomandi M, Brown JK, et al. Risk assessment for indeterminate pulmonary nodules using a novel, plasma-protein based biomarker assay. Biomed Res Clin Pract. Dec 2018; 3(4). PMID32913898
12. 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. PMID 37432960
13. 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): e142S-e165S. PMID 23649436
14. Whitney DH, Elashoff MR, Porta-Smith K, et al. Derivation of a bronchial genomic classifier for lung cancer in a prospective study of patients undergoing diagnostic bronchoscopy. BMC Med Genomics. May 06 2015; 8: 18. PMID 25944280
15. Silvestri GA, Vachani A, Whitney D, et al. A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. N Engl J Med. Jul 16 2015; 373(3): 243-51. PMID 25981554
16. Vachani A, Whitney DH, Parsons EC, et al. Clinical Utility of a Bronchial Genomic Classifier in Patients With Suspected Lung Cancer. Chest. Jul 2016; 150(1): 210-8. PMID 26896702
17. Ferguson JS, Van Wert R, Choi Y, et al. Impact of a bronchial genomic classifier on clinical decision making in patients undergoing diagnostic evaluation for lung cancer. BMC Pulm Med. May 17 2016;16(1):
18. PMID 27184093
19. 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. PMID 23649434
20. Mazzone PJ, Sears CR, Arenberg DA, et al. Evaluating Molecular Biomarkers for the Early Detection of Lung Cancer: When Is a Biomarker Ready for Clinical Use? An Official American Thoracic Society Policy Statement. Am J Respir Crit Care Med. Oct 01 2017; 196(7): e15-e29. PMID 28960111
21. National Comprehensive Cancer Network. NCCN Guidelines Version 3.2025: Non-Small Cell Lung Cancer. 2024; https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 27,
23. National Comprehensive Cancer Network. NCCN Guidelines Version 4.2025: Small Cell Lung Cancer.2023; https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed March 25, 2025.

24. Biodesix. Nodify Lung: Lung Nodule Management. 2024; https://www.biodesix.com/our-tests/nodify- lung. Accessed March 27, 2025.

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