CurrentCapital BluecrossPolicy MP 2.337

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

This policy governs coverage of proteomic testing (e.g., VeriStrat) for management and therapy selection in non-small-cell lung cancer (NSCLC) for Capital BlueCross members and specifies that such testing is investigational.

Policy Summary

PayerCapital Bluecross

PolicyProteomic Testing for Targeted Therapy in Non‑Small Cell Lung Cancer

Policy CodePolicy MP 2.337

Change TypeNo material change

Effective Date12/1/2025

Next Review DateN/A

Key ActionDo not authorize coverage for proteomic testing (including VeriStrat, CPT 81538) for NSCLC because it is investigational.

SourceLink

investigationalcoverage stance for proteomic testing (including VeriStrat)

12/1/2025Effective date

MP 2.337Policy number

81538Investigational procedure

InsufficientEvidence conclusion

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Coverage Determinations

Investigational — Proteomic testing (including VeriStrat)

Not covered (investigational) when ALL of the following apply:

Proteomic testing investigational: 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.

There is insufficient evidence to support improved net health outcomes or clinical utility.

Not covered — investigational (policy determination summary)

Policy determination summary

Investigational stance: Use of serum proteomic tests (eg, VeriStrat) to predict survival or to select therapy for NSCLC is considered investigational due to insufficient evidence of improved net health outcomes.

Supported by multiple retrospective studies, some randomized trials, and analyses concluding evidence is insufficient to demonstrate clinical benefit.

The policy states that proteomic testing, including the VeriStrat assay, is investigational for all uses in the management of non‑small‑cell lung cancer (NSCLC). There are no covered indications listed for proteomic testing in NSCLC under this policy; requests for such testing will be reviewed and denied as investigational consistent with the policy statement.

The evidence review did not identify published studies that used VeriStrat proteomic testing to inform therapeutic options for patients with stage I or II NSCLC after surgery (or surgery plus radiotherapy) or for patients with medically inoperable stage I or II disease. Therefore, the policy does not support use of VeriStrat to guide postoperative or early‑stage management decisions.

Because proteomic testing is classified as investigational in this policy, it is not considered medically necessary for selection of targeted therapy in NSCLC. The policy specifically notes insufficient evidence that proteomic testing improves net health outcomes, and thus proteomic results should not be used as the basis for therapy selection in place of established molecular testing.

The policy concludes that the current evidence is insufficient to demonstrate improvement in net health outcomes from proteomic testing in NSCLC. The evidence base includes retrospective studies, some randomized data, and prospective collections, but these do not show consistent clinical utility for guiding treatment decisions or improving survival outcomes.

Covered indications — None (investigational)

No covered indications for proteomic testing in NSCLC; declared investigational.

Covered indications: There are no indications for which proteomic testing (including VeriStrat) is listed as a covered service for management of non-small-cell lung cancer.

Proteomic testing is considered investigational for all uses in NSCLC.

Not covered — proteomic testing not covered for prognostic or predictive use in NSCLC.

None — proteomic testing not covered for prognostic or predictive use in NSCLC.

Not covered — prognostic or predictive use: Serum proteomic testing (for example, VeriStrat) is not covered when used to predict survival or to select systemic or targeted therapy in patients with NSCLC.

CPT code 81538 (VeriStrat) is categorized as investigational and not covered.

Advanced NSCLC — evidence context for proteomic testing (EGFR-targeted therapy)

Advanced NSCLC (stage IIIB/IV) considered for EGFR-targeted therapies — studies evaluated proteomic tests for prognosis/prediction.

Context of evidence: Multiple studies (including randomized trials such as PROSE and EMPHASIS and retrospective analyses) evaluated VeriStrat as a prognostic or predictive classifier in patients with advanced (stage IIIB/IV) NSCLC treated with EGFR-targeted therapies such as erlotinib.

These studies did not establish that proteomic classification improves net health outcomes or should replace molecular variant testing.

Covered Indications

Covered indications — None (investigational)

No covered indications for proteomic testing in NSCLC; declared investigational.

Covered indications: There are no covered indications for proteomic testing (including VeriStrat) in the management of non-small-cell lung cancer.

Proteomic testing is considered investigational for all uses in NSCLC.

Not covered — proteomic testing not covered for prognostic or predictive use in NSCLC.

None — proteomic testing not covered for prognostic or predictive use in NSCLC.

Not covered — prognostic or predictive use: Serum proteomic testing (eg, VeriStrat; CPT 81538) is investigational and not covered for predicting survival or selecting targeted/systemic therapy in NSCLC.

Evidence is insufficient to demonstrate clinical utility or improved net health outcomes.

Advanced NSCLC — study and therapy context

Advanced non-small cell lung cancer (stage IIIB/IV) considered for EGFR-targeted therapies such as erlotinib — referenced study contexts.

EGFR-targeted therapy context: Studies assessing proteomic tests evaluated patients with advanced non-small-cell lung cancer (stage IIIB or IV) in the context of EGFR-targeted therapy trials; selection of EGFR TKIs should be based on established EGFR variant testing rather than proteomic results.

Guideline-recommended variant testing (EGFR) is preferred prior to selecting TKI therapy.

Provider Actions and Billing Guidance

Denial Risk

Investigational — Not Covered

Requests for proteomic testing (including VeriStrat and other proteomic classifiers) for use in the management of non‑small cell lung cancer are investigational and not covered. Such requests will be denied as investigational and are not eligible for reimbursement.

Note

Refer to Cross‑Referenced Molecular Testing Policies

If coverage of a molecular or proteomic test is requested but is not specifically addressed in this policy, refer to the cross‑referenced molecular testing policies for guidance. Relevant policies include MP 2.259 (Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies) and MP 2.241 (Molecular Analysis for the Targeted Therapy for Non‑Small Cell Lung Cancer).

Prior Authorization

Determine EGFR Variant Status Before Selecting EGFR TKI

Determine EGFR sensitizing variant status (and other guideline‑recommended molecular biomarkers) before selecting an EGFR tyrosine kinase inhibitor following disease progression or recurrence. Proteomic testing is not a substitute for standard molecular testing to identify actionable variants that guide targeted therapy selection.

Providers should perform guideline‑recommended molecular testing for EGFR and other relevant biomarkers prior to initiating or changing targeted EGFR TKI therapy.
Do not use proteomic test results in place of validated molecular variant testing when choosing EGFR‑directed treatments.

Definitions

inv-23: Proteomic testing — assays analyzing protein signatures proposed to predict survival or treatment response in NSCLC.

DefinitionAssays analyzing protein signatures proposed to predict survival outcomes or treatment response in non-small-cell lung cancer (NSCLC).

Clinical contextProposed to predict survival and response to targeted therapy (eg, EGFR TKIs) in NSCLC; VeriStrat is one commercially available assay studied for this purpose.

Specimen typesSerum or other bodily fluids (eg, blood, pleural fluid) have been used to derive proteomic signatures for cancer activity assessment.

Analytic platformsMass spectrometry (eg, MALDI-TOF) or protein microarray methods are used to measure proteomic profiles.

inv-24: EGFR variants and ALK rearrangements — established biomarkers guiding targeted therapies.

EGFR variants (examples)Exon 19 deletions and exon 21 L858R point mutation — sensitize tumors to EGFR tyrosine kinase inhibitors (eg, erlotinib).

ALK rearrangementsEML4-ALK fusion (inversion on chromosome 2p) leads to ligand-independent ALK activation and is a target for ALK inhibitors (eg, crizotinib).

Prevalence notesEGFR variant prevalence varies by population; up to 30–50% in nonsmoking Asian women with adenocarcinoma and ~15% in US lung adenocarcinoma patients; ALK fusions occur in ~2–7% of US patients.

inv-25: Proteome / proteomics definition.

Proteome (definition)The entire complement of proteins produced by an organism or cellular system; proteomics is the large-scale study of that proteome.

Biologic variabilityThe proteome may differ between cell types and over time and can change in response to stressors or disease processes.

Measurement methodsMeasured by mass spectrometry or protein microarrays; tumor or bodily-fluid proteomic signatures have been investigated as cancer biomarkers.

inv-26: VeriStrat — serum-based MALDI MS test producing 'good' or 'poor' classification from an 8-peak signature.

Test name and platformVeriStrat — a serum-based assay using matrix-assisted laser desorption ionization (MALDI) mass spectrometry analysis and a proprietary classification algorithm.

Classification outputBinary result reported as 'Good' or 'Poor'.

Signature detailsBased on an 8-peak proteomic signature; four of the eight peaks have been identified as fragments of serum amyloid A protein 1.

inv-27: VeriStrat — serum-based proteomic test used to classify NSCLC patients for prognosis or prediction of response to EGFR-targeted therapies.

Intended use studiedUsed to classify patients with NSCLC for prognostic purposes and as a predictive classifier for response to EGFR-targeted therapies (EGFR TKIs) in multiple studies and trials.

Regulatory/analytic contextOffered as a laboratory-developed, serum-based proteomic test; classification algorithm developed and validated on multiple patient cohorts.

Clinical evidenceMultiple retrospective studies and randomized trials (eg, PROSE) and other cohort studies have evaluated VeriStrat as a prognostic/predictive tool in NSCLC treated with EGFR-TKIs.

Policy Revision History

2025-10-29Administrative updateLatest

Removed Benefit Variations section and updated Disclaimer; no change to clinical policy statement.

2024-09-23Consensus review

References reviewed and updated; no change to clinical policy statement and no coding changes.

2023-09-27Consensus review — coding update

Coding table and references updated; HCPCS code 0080U removed from the policy because it does not apply to cancer management.

2022-10-04Consensus review

No change to clinical policy statement; NCCN language added and cross-referenced policies updated; background, rationale, and references updated.

2021-04-07Consensus review

Description/Background updated and references updated; no change to clinical policy statement.

2020-07-20Consensus review

Reference updates performed; no changes to the clinical policy statement.

OpenPayer

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

Coverage Determinations

Covered Indications

Not Covered / Investigational

Procedure Codes and Coding Notes

Provider Actions and Billing Guidance

Definitions

Background and Evidence Summary

Policy Revision History