MolDX: Percepta© Bronchial Genomic Classifier

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

Title XVIII of the Social Security Act, §1833(e), prohibits Medicare payment for any claim lacking the necessary documentation to process the claim. 42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests:
Conditions.

CMS Internet Only Manuals, Publication 10004, Medicare Claims Processing Manual¨ Ch. 16, §50.5 Jurisdiction of Laboratory Claims, 60.12 Independent Laboratory Specimen Drawing, 60.2. Travel Allowance.

This Medicare contractor will provide limited coverage for the Percepta Bronchial Genomic Classifier (Veracyte, Inc., South San Francisco, CA) to identify patients with clinical low- or intermediate-risk of malignancy, after a non-diagnostic bronchoscopy, who may be followed with CT surveillance in lieu of further invasive biopsies or surgery. A patient’s clinical risk of malignancy may be ascertained by the McWilliams or Gould risk assessment models. Coverage does not include clinical high risk patients or patients with known lung cancer.

Lung cancer is the leading cause of cancer deaths in the United States¹. New screening programs are expected to save lives through early detection, but are also expected to increase the number of patients who undergo invasive procedures to evaluate suspicious lung nodules and lesions².

Traditionally, following the identification of a suspicious lung nodule or lesion, clinical characteristics are utilized to determine risk and to determine whether patients should proceed to an invasive biopsy. Clinical characteristics that have statistically correlated with a higher risk of malignancy in risk assessment models include older age, smoking history, nodule size and speculation^{3, 4}. Anatomic location, solid versus part-solid or non-solid characteristics, and time since smoking discontinuation have had less consistent correlation. However, variation in cohort demographics and data availability used in developing these models, including prevalence of malignancy (3.7% to 54%), have challenged consistent utilization of these models when used alone in clinical practice.

The American College of Chest Physicians published clinical guidelines in 2013 to assist clinicians with assigning risk allocation⁵.

Table 1: American College of Chest Physicians (ACCP) – Assessment of the probability of malignancy based on clinical factors alone⁵.

At the current time, in the absence of definitive guidelines, patients assigned with a physician-assessed low or intermediate risk for malignancy may be considered for serial CT surveillance or invasive biopsy⁵, and many of these patients ultimately undergo surgery for benign disease⁶.

Newer predictive models, which incorporate a number of radiological and clinical features to predict malignancies, may be more predictive than physician assessment alone in preventing invasive procedures in patients with benign nodules^{3, 4}. Even with these risk models, supplementary methods to improve diagnostic accuracy are important to prevent unneeded morbidity, mortality and costs from invasive procedures, without increasing the risk of missing a malignancy.

Bronchoscopy is a non-surgical diagnostic method that enables physicians to visualize and collect cells from the patient’s lung airways. An estimated 250,000 patients undergo bronchoscopy each year in the United States to evaluate lung nodules that are suspicious for cancer⁷. Up to 40% of bronchoscopy procedures result in a non-diagnostic outcome, which means the clinician could not reach a clinically actionable benign or malignant diagnosis⁴. Physicians are then faced with the dilemma of whether to monitor these patients with CT surveillance or proceed to a surgical lung biopsy or transthoracic needle biopsy associated with a greater risk of morbidity, such as pneumothorax or hemorrhage, or mortality^{8, 9}.

Percepta™ Bronchial Genomic Classifier (Percepta BGC) Test Description and Performance

The Percepta BGC is a messenger-RNA assay measuring gene expression of 23 lung cancer associated genes and patient age. The assay is performed on cytology brushings of bronchial epithelial cells collected during a bronchoscopy from the main stem bronchus and stored in an RNA preservative at 4°C immediately after collection. The assay results are reported as a categorical result based on the patient’s physician-assessed pretest risk of malignancy as described below.

Table 2: Percepta Classifier Results

The clinical performance of Percepta BGC has been demonstrated in two prospective-retrospective, multicenter and blinded trials^{8, 10}. The results from these trials showed that the classifier is able to detect cancer with a high sensitivity exceeding the performance of bronchoscopy alone¹¹. In the low and intermediate pretest risk groups, negative classifier results identified patients at a low risk of malignancy with a high negative predictive value (NPV) of 100% (95% CI 89-100%) and 91% (95% CI 75-98%), respectively, who may be followed with CT surveillance in lieu of further invasive investigation.

The analytical and clinical performance of the Percepta BGC is summarized below.

General

Analytical Performance

¹Using Clopper-Pearson method

Clinical Performance

*Using Clopper-Pearson method

The usefulness of the assay in the low and intermediate pretest risk groups has been evaluated in two additional modeling studies¹³. These studies suggest that use of the classifier may safely reduce invasive surgical procedures among patients with a low or intermediate pretest risk following a non-diagnostic bronchoscopy. This Medicare contractor is aware that Veracyte is also currently running the PERCEPTA Registry Trial to prospectively evaluate the clinical utility of the classifier.

The potential usefulness of this test is that it allows physicians to determine which patients with a low or intermediate physician-assessed pretest risk and a non-diagnostic bronchoscopy may be candidates for CT surveillance in lieu of further invasive biopsies or surgical procedures.

Criteria for Coverage

Percepta BGC is covered only when the following clinical conditions are met:

• Current or former smokers age 21 and greater, and
• Physician-assessed low or intermediate pretest risk of malignancy based upon the following clinical characteristic stratification^{3, 4}, and:

• Bronchoscopy is non-diagnostic (actionable benign or malignant diagnosis cannot be reached), and
• Percepta BGC results will be utilized to determine whether CT surveillance is appropriate in lieu of further invasive biopsies or surgical procedures as outlined below, and

• Test is ordered by physician certified in Percepta Certification and Training Registry (CTR), and
• Patient is monitored for malignancy (suggested monitoring includes serial CT scans at 3 to 6, 9 to 12, and 18 to 24 months, using thin sections and non-contrast, low-dose techniques), and
• Physician will report outcomes in all risk groups including those monitored initially and those who undergo immediate intervention, and
• Clinical management is consistent with the post-test diagnostic strategy described above in ≥80% of tested patients.

Note: The Percepta BGC test should not be ordered if a physician does not intend to act upon the test result.

Certification and Training Registry Program

The Percepta® Bronchial Genomic Classifier will be made available only to Medicare patients through physicians who participate in a MolDx approved Percepta Certification and Training Registry (CTR) program. This CTR serves to assure the appropriate selection of patients and follow-up to ensure the benefits of the test outweigh its risks. As part of this requirement Veracyte will provide to this Medicare contractor reports every 6 months in a mutually agreed upon format. The CTR will continue for 36 months from the issuance of the final LCD or the presentation of prospective data demonstrating the clinical utility and safety of the assay.

The goals of the Percepta CTR program are as follows:

• To inform physicians and patients on the safe use of Percepta BGC, and
• To ensure that physicians understand the limitations of the test based on its validation studies, and
• Make a good faith effort to identify any safety concerns from the use of the test, and
• To identify the clinical utility of the Percepta BGC test in the intended use patient population.

This Medicare contractor expects Veracyte to:

• Establish and maintain the Percepta Certification and Training Registry (CTR);
• Ensure that healthcare providers who order the Percepta BGC assay are registered and certified in the Percepta CTR program and that the Percepta BGC assay is available only through these providers for Medicare patients;
• Report utilization data by final Percepta risk group;
• Report clinical outcomes in each Percepta risk group;
• Report all patients receiving a “Low or “Very Low” Percepta BGC assay result who are diagnosed with cancer during the CTR program;
• Share all required data and reports in a HIPAA complaint fashion;
• Publish final results in a peer-reviewed scientific journal with an impact factor of ≥4.5.

 Level of Evidence:

Quality – Moderate

 Strength – Limited

 Weight - Limited

This contractor recognizes that evidence for clinical utility for Percepta Bronchial Genomic Classifier to identify patients with clinical low- or intermediate-risk of malignancy after a non-diagnostic bronchoscopy is promising at the current time. This contractor is aware that Veracyte is currently running the PERCEPTA Registry Trial to prospectively evaluate the clinical safety and utility of the classifier. Veracyte will continue to accrue patients in the PERCEPTA Registry Trial and, at interim analyses, demonstrate that in intended-use patients whose post-test risk is very low- or low that there is a statistically significant decrease in the rate of nodule progression as compared to current screening standards.  There is no coverage for pretest ‘High Risk’ patients or ‘never smokers’.  Continued coverage for the Percepta assay will be dependent on semi-annual review of interim data and/or peer-reviewed publications  of clinical utility data demonstrates decreased nodule progression and that patients can be followed with CT surveillance in lieu of further invasive biopsies or surgery.

Noridian did not receive any comments for the draft LCD, comment period ending 12/15/16.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: A Cancer Journal for Clinicians. 2015;65(1):5–29.

2. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. NEJM 2011;365(5):395–409.

3. Gould MK, Ananth L, Barnett PG, Veterans Affairs SNAP Cooperative Study Group. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest. 2007;131(2):383–8.

4. McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of Cancer in Pulmonary Nodules Detected on First Screening CT. NEJM 2013;369(10):910–9.

5. 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 2013;143;e93S–120S.

6. Tanner NT, Aggarwal J, Gould MK, et al. Management of pulmonary nodules by community pulmonologists: a multicenter observational study. Chest 2015;148(6):1405–14.

7 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 2013;143(5 Suppl):e142S–65S.

8. Silvestri GA, Vachani A, Whitney D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. NEJM 2015;373(3):243–51.

9. Ost D, Fein AM, Feinsilver SH. Clinical practice. The solitary pulmonary nodule. NEJM 2003 ;348(25):2535–42.

10. Wiener RS, Wiener DC, Gould MK. Risks of transthoracic needle biopsy: How high?. Clin Pulm Med 2013;20(1):29–35.

11. 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 Medical Genomics. 2015;8(1):18.

12 Anil Vachani MM, Duncan H Whitney P, Edward C Parsons P, Marc Lenburg P, J Scott Ferguson MD, Gerard A Silvestri MM, et al. Clinical Utility of a Bronchial Genomic Classifier in Patients with Suspected Lung Cancer. Chest. Elsevier Ltd; 2016 Feb 15;:1–21.

13. Ferguson JS. Impact of a bronchial genomic on clinical decision making in patients undergoing diagnostic evaluation for lung cancer. BMC Pulmonary Medicine. 2016 Apr 11;:1–25.