ModifiedCapital BluecrossPolicy MP 2.241

Somatic biomarker testing (including liquid biopsy) for targeted treatment in non-small-cell lung cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK)

Defines medical necessity and investigational uses for tumor tissue and plasma (ctDNA) testing of specific somatic biomarkers to guide FDA‑approved targeted therapies in advanced or metastatic NSCLC.

Policy Summary

PayerCapital Bluecross

PolicySomatic biomarker testing (including liquid biopsy) for targeted treatment in NSCLC

Policy CodePolicy MP 2.241

Change TypeCoding and coverage-status updatesinvestigational/medically necessary code reclassifications

Effective Date10/01/2025

Next Review Date

Key ActionDocument tissue sufficiency and obtain prior authorization when required; use listed covered codes for tissue testing and avoid investigational codes that will be denied.

SourceLink

POLICY UPDATE CHANGES

Extensive changes to policy statement with minor changes to intent; Agilent Resolution test with code 0179U will now be medically necessary (MN) from investigational (INV); removed statements regarding tumor mutational burden testing and PD-L1 testing, moved Lung HDPCR test and code 0478U to MP 2.326; removed statement regarding HER2 testing; added codes 0388U and 0530U as INV.

New code 0585U added effective 10/01/2025 as part of new code process.

Added FoundationOne as medically necessary for liquid biopsy testing; added MN statement for liquid biopsy testing for ALK, ROS1, KRAS, HER2, and MET.

Plasma testing when tissue is insufficient was added as medically necessary with criteria.

10/01/2025Effective date listed

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Coverage Criteria for Somatic Biomarker Testing

ctDNA evidence limitations

ctDNA (plasma/cell‑free DNA) testing has important limitations that affect its use as a substitute for tissue-based testing. The following summarizes evidence-based limitations and operational considerations relevant to coverage determinations.

Liquid biopsy (ctDNA) has high specificity but appreciable false‑negative rates; a negative ctDNA result does not reliably exclude the presence of a tissue-detected driver alteration and therefore should not be used alone to rule out actionable variants when tissue is available and sufficient for testing.

The sensitivity of ctDNA assays is influenced by tumor burden, anatomical site of disease, and biological shedding. Low-volume disease, isolated central nervous system metastases, and certain histologies may have low ctDNA shedding and increase the risk of false-negative results.

ctDNA assays vary in analytic performance across platforms and variants evaluated. Not all ctDNA tests are FDA‑cleared/approved as companion diagnostics for specific therapy indications; when using plasma testing to select FDA‑labeled therapy, an FDA‑approved companion diagnostic for that indication is preferred and, when available, required by this policy for covered use.

ctDNA can detect somatic variants that are subclonal or derived from clonal hematopoiesis of indeterminate potential (CHIP); variant interpretation requires correlation with clinical context and, when indicated, confirmatory tissue testing or paired white‑blood‑cell sequencing to exclude CHIP-origin variants.

ctDNA testing is useful for rapid initial genotyping and for detecting acquired resistance mutations at progression (for example, EGFR T790M), but when a ctDNA result is negative or discordant with clinical suspicion, tissue testing should be pursued if feasible.

Concurrent or reflex testing strategies (performing both tissue and plasma testing) may be reasonable to increase yield or shorten time-to-result; however, concurrent testing may lead to discordant results and requires documentation of clinical intent and a plan for how discordant findings will be reconciled.

Evidence for clinical utility of ctDNA testing varies by gene/alteration and by intended therapeutic decision; the policy limits covered ctDNA use to situations where (1) an FDA‑approved plasma companion diagnostic exists for the specific gene/variant and indicated therapy, or (2) where NCCN (or comparable guideline) recommendations explicitly support plasma testing as an alternative to tissue for that gene/variant.

Repeat ctDNA testing may be appropriate to assess acquired resistance when guided by clinical change or progression and when results would change management; routine serial ctDNA testing for surveillance in the absence of actionable management implications is not supported by current evidence.

When tissue is insufficient for standard molecular testing, ctDNA testing may be used as an alternative provided there is a plan for follow-up tissue-based analysis if no driver variant is identified via plasma testing.

Covered Indications and Clinical Context

Detection of specific somatic variants/fusions (EGFR exons 18–21 and exon 20 insertions; ALK; BRAF V600E; ROS1; KRAS G12C; RET; MET exon 14; NTRK)

Detection of specific somatic variants/fusions to predict response to FDA‑approved targeted therapies:

Targetable alterations: Detection of EGFR (exons 18–21 and exon 20 insertions), ALK rearrangements, BRAF V600E, ROS1 rearrangements, KRAS G12C, RET alterations, MET exon 14 skipping, and NTRK fusions is medically indicated to predict response to the corresponding FDA‑approved targeted therapies in individuals with advanced or metastatic NSCLC when use is consistent with FDA labeling and no FDA‑labeled contraindications exist.

Individuals with NSCLC who meet testing criteria to identify targetable somatic variants to guide targeted therapy or immunotherapy

Individuals with NSCLC who meet testing criteria to identify targetable somatic variants to guide therapy:

Eligible population: Individuals with NSCLC who meet testing criteria to identify targetable somatic variants to guide targeted therapy or immunotherapy; when tumor tissue is available, tissue testing is recommended but liquid biopsy may be used in select situations.

Not Covered / Investigational Uses

The policy explicitly states that plasma (ctDNA) testing is investigational and not covered as an alternative to tissue for several biomarkers in many contexts — including BRAF V600E, ROS1 rearrangements, and RET alterations — except where an FDA‑approved plasma companion diagnostic or other specific policy criteria allow plasma testing.

For biomarkers where the policy permits plasma testing, that allowance is limited to the narrow circumstances described (for example, select FDA‑approved companion diagnostic plasma tests or when tissue is insufficient and follow‑up tissue analysis is planned).

Per the cited guideline, genes that are not part of the minimum set (EGFR, ALK, ROS1) or the recommended expanded panel (BRAF, MET, RET, ERBB2/HER2, KRAS) were considered investigational at the time the guideline was published; the policy applies this guidance when evaluating coverage for genes outside those panels.

The policy’s CODING section identifies particular procedure codes as investigational and not covered for geneTMB and specific cell‑free DNA (cfDNA) assays (see coding table: examples include 81404, 81405, 81479 for geneTMB and proprietary cfDNA codes such as 0388U, 0409U, 0436U, 0485U, 0530U).

Providers should use the covered procedure codes listed in the policy when tests meet medically necessary criteria and avoid use of the investigational codes for claims intended to be covered.

The policy reiterates that ordering or billing using the procedure codes designated as investigational for geneTMB or specified proprietary cfDNA assays will result in those services being not covered under this policy.

Coding and Billing

Investigational; therefore not covered when used to test for genetic alterations in the geneTMB for targeted therapy in patients with NSCLCCPTNot Covered

81404	Procedure code listed as investigational; not covered when used to test for genetic alterations in the geneTMB for targeted therapy in patients with NSCLC
81405	Procedure code listed as investigational; not covered when used to test for genetic alterations in the geneTMB for targeted therapy in patients with NSCLC
81479	Unlisted molecular pathology procedure — listed as investigational; not covered when used to test for genetic alterations in the geneTMB for targeted therapy in patients with NSCLC

Investigational; therefore not covered for cell-free DNA testingCPT/HCPCSNot Covered

0388U	Listed investigational; not covered for cell-free DNA testing
0409U	Listed investigational; not covered for cell-free DNA testing
0436U	Listed investigational; not covered for cell-free DNA testing
0485U	Listed investigational; not covered for cell-free DNA testing
0530U	Listed investigational; not covered for cell-free DNA testing

Investigational; not covered for geneTMBCPTNot Covered

81404	Procedure code listed as investigational for geneTMB testing
81405	Procedure code listed as investigational for geneTMB testing
81479	Unlisted molecular pathology procedure — listed as investigational for geneTMB testing

Investigational; not covered for cell-free DNA testingCPTNot Covered

0388U	Proprietary cfDNA procedure code listed as investigational / not covered
0409U	Proprietary cfDNA procedure code listed as investigational / not covered
0436U	Proprietary cfDNA procedure code listed as investigational / not covered
0485U	Proprietary cfDNA procedure code listed as investigational / not covered
0530U	Proprietary cfDNA procedure code listed as investigational / not covered

Covered when medically necessary (tissue testing) and covered for plasma/cell-free DNA when tissue insufficientmixedCovered

81191	Covered when medically necessary (tissue testing)
81192	Covered when medically necessary (tissue testing)
81193	Covered when medically necessary (tissue testing)
81194	Covered when medically necessary (tissue testing)
81210	Covered when medically necessary (tissue testing)
81235	Covered when medically necessary (tissue testing)
81275	Covered when medically necessary (tissue testing)
81276	Covered when medically necessary (tissue testing)
81401	Covered when medically necessary (tissue testing)
81404	Also listed among covered when medically necessary (tissue testing)

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ICD-10 diagnosis codes referencedICD-10

C34.00	Malignant neoplasm of unspecified main bronchus
C34.01	Malignant neoplasm of right main bronchus
C34.02	Malignant neoplasm of left main bronchus
C34.10	Malignant neoplasm of upper lobe, unspecified bronchus or lung
C34.11	Malignant neoplasm of upper lobe, right bronchus or lung
C34.12	Malignant neoplasm of upper lobe, left bronchus or lung
C34.2	Malignant neoplasm of middle lobe, bronchus or lung
C34.30	Malignant neoplasm of lower lobe, unspecified bronchus or lung
C34.31	Malignant neoplasm of lower lobe, right bronchus or lung
C34.32	Malignant neoplasm of lower lobe, left bronchus or lung

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Policy-specific genomic test codes and status changesmixed

0326U	Code added as medically necessary (per history entry)
0334U	Code added effective 10/01/2022
0436U	Code added as investigational (INV) on 12/12/2023
0473U	Added as MN effective 07/01/2024
0478U	New code added effective 10/01/2024; Lung HDPCR assigned code 0478U (later moved to MP 2.326)
0485U	New code added effective 10/01/2024
0409U	Added as INV (10/28/2024)
0179U	Agilent Resolution test code changed to MN (03/28/2025)
0388U	Added as INV (03/28/2025)
0530U	Added as INV (03/28/2025)

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Specimen sufficiency — plasma/cell-free DNA testing covered when tissue is insufficient

Policy rulePlasma/cell-free DNA testing is covered when tumor tissue is insufficient for standard FFPE molecular testing and follow-up tissue-based analysis is planned if no driver variant is found.

Condition 1Individual does not have sufficient tissue for standard molecular testing using formalin-fixed paraffin-embedded (FFPE) tissue.

Condition 2Follow-up tissue-based analysis is planned should no driver variant be identified via plasma testing.

Coding noteUse listed plasma/cfDNA procedure codes (e.g., 81455 and mapped codes) when covered for tissue-insufficient indications per coding section.

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Prior Authorization May Be Required

Product-specific prior authorization may be required depending on the Capital Blue Cross product and member benefit. This policy applies only to certain programs and products administered by Capital Blue Cross; providers should verify prior authorization requirements against the member's benefit plan before ordering testing.

Product-specific prior authorization may be required — check member benefit and product.
This policy applies only to certain programs/products administered by Capital Blue Cross.

Denial Risk

Investigational Codes and Prior Authorization

Certain molecular test procedure codes listed as investigational in the coding section are associated with denial when used for the indications described (for example, some cfDNA and geneTMB tests). Providers must obtain prior authorization when required by the member's benefit; absence of prior authorization when required may result in denial or delayed payment.

Definitions and Background

Somatic tumor profiling—performed on tumor tissue or via plasma cell‑free DNA (ctDNA)—is used to identify driver and resistance variants that predict response to FDA‑approved targeted therapies in advanced or metastatic NSCLC. These assays support selection of targeted agents when the test result is consistent with FDA labeling and companion diagnostic indications.

Plasma‑based companion diagnostic tests can serve as an alternative to tissue testing in limited circumstances (e.g., when tissue is insufficient or biopsy is not feasible), but tissue testing is generally preferred when available; follow‑up tissue testing is recommended if plasma testing is negative and tissue is obtainable.

Broad molecular profiling definition

DefinitionBroad molecular profiling: A single assay or combination of a limited number of assays to evaluate multiple clinically relevant biomarkers in NSCLC; acceptable to use a tiered approach for low-prevalence co-occurring biomarkers per NCCN guidance.

PurposeUsed to identify actionable somatic variants (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK) to guide targeted therapy selection.

Panel contentMinimum panel should include EGFR, ALK, and ROS1; expanded panels may include BRAF, MET, RET, ERBB2 (HER2), and KRAS when material allows.

Eligibility Requirements

No top‑level eligibility requirement nodes are specified in the brief for this policy; eligibility is determined by the clinical indications and per‑gene coverage criteria described elsewhere in the policy.

There are no additional standalone eligibility requirement statements extracted as top‑level items in the brief; coverage depends on meeting the policy’s per‑gene and specimen‑specific criteria and applicable member benefit terms.

The policy does not enumerate separate pre‑test eligibility pathways as top‑level nodes in the brief; clinical eligibility is assessed according to the defined medically necessary indications for the requested biomarker test.

No distinct prior‑testing or sequencing eligibility requirements are supplied as top‑level brief nodes; when relevant, the policy references tissue sufficiency and FDA companion diagnostic labeling to determine acceptable test use.

The brief did not extract any additional top‑level eligibility criteria; use of tests is judged against the per‑gene criteria, companion diagnostic status, and documentation of tissue sufficiency where plasma testing is proposed.

There are no separate eligibility requirement items captured as top‑level nodes in the brief; reviewers should apply the gene‑specific and specimen‑specific coverage rules in this policy to determine member eligibility for testing.

Policy Revision History

2025-10-01code_addedLatest

New HCPCS/CPT code 0585U added to the policy (administrative update).

2022-02-02major_review

Denial statements were expanded into separate statements during the major review that merged MP 2.283 into this policy and revised ctDNA-related criteria.

2023-07-31

Policy Summary

PayerCapital Bluecross

PolicySomatic biomarker testing (including liquid biopsy) for targeted treatment in NSCLC

Policy CodePolicy MP 2.241

Change TypeCoding and coverage-status updatesinvestigational/medically necessary code reclassifications

Effective Date10/01/2025

Next Review Date

Key ActionDocument tissue sufficiency and obtain prior authorization when required; use listed covered codes for tissue testing and avoid investigational codes that will be denied.

SourceLink

On This Page

Advanced or metastatic NSCLC patients being considered for FDA-approved targeted therapy where identification of somatic alterations will guide therapy selection

Advanced or metastatic NSCLC patients being considered for FDA‑approved targeted therapy where identification of somatic alterations will guide therapy selection:

Advanced/metastatic NSCLC consideration: Advanced or metastatic NSCLC patients being considered for FDA‑approved targeted therapy where identification of somatic alterations (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK) will guide therapy selection; coverage is supported where FDA‑approved companion diagnostics exist and/or NCCN recommendation level is 2A or higher.

Supported by randomized trials and FDA CDx summaries for tissue and plasma assays

Supported by randomized trials and FDA CDx summaries for tissue and plasma assays:

Evidence support: Detection of actionable somatic alterations in advanced NSCLC to guide selection of targeted therapies (including EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK) using tissue and/or plasma ctDNA assays is supported by randomized trials and FDA companion diagnostic summaries cited in the evidence base.

Molecular profiling to identify actionable driver and resistance mutations — notes on tissue NGS and FDA-approved liquid biopsy CDx

Molecular profiling to identify actionable driver and resistance mutations — notes on tissue NGS and FDA-approved liquid biopsy CDx:

Molecular profiling to identify actionable driver and resistance mutations in advanced NSCLC is clinically useful; tissue NGS and selected FDA‑approved liquid biopsy companion diagnostics (e.g., FoundationOne Liquid CDx, Guardant360 CDx) are referenced as validated approaches when used per FDA labeling.

The policy history records movement and status updates for specific platforms and tests that were at times listed as investigational; one example referenced in recent history is the reassignment or movement of Lung HDPCR (code 0478U) and other code changes tracked across the policy history entries.

Because platform status and code assignments have changed over time, providers should consult the policy history for the effective dates and current coverage status of individual platform codes.

Billing Rule

Use Specified Covered Codes When Medically Necessary

Use the specified covered procedure codes when testing is medically necessary. Coverage of a listed code depends on the member's benefit and documentation of medical necessity. When submitting claims, code according to the effective dates and the policy history updates.

Submit tissue-based testing using the listed covered CPT/proprietary codes when medically necessary.
Submit plasma / cfDNA testing using the listed covered CPT/proprietary codes when medically necessary or when tissue is insufficient.
Coverage determination depends on member benefit; identification of a code here does not guarantee payment.

Prior Authorization

Prior Authorization Not Specified in Policy Excerpt

This policy excerpt does not specify a single product-wide prior authorization rule; prior authorization requirements vary by Capital Blue Cross product and member benefit. Providers should verify prior authorization needs with the member’s plan and obtain authorization when the benefit requires it.

No single prior authorization rule specified in this policy excerpt — check product/benefit.
If prior authorization is required by the member’s plan, obtain it before ordering tests.

Note

Coding and Prior Authorization Updates

Providers are responsible for coding and prior authorization updates reflected in the policy history. Codes (CPT and proprietary) have been added, removed, or had status changes on multiple dates; always verify code applicability and effective dates before billing.

Policy history documents coding updates (e.g., additions of 81191–81194, 0326U, 0334U, 0436U, 0473U, 0478U, 0485U, 0585U and others).
Code status (MN vs INV) has changed over time — verify current status and effective dates.

Denial Risk

Tests Inconsistent with FDA-Approved Companion Diagnostic Labeling

Tests that are inconsistent with FDA-approved companion diagnostic labeling for the intended therapeutic agent may be denied. When an FDA-approved companion diagnostic exists for a therapy, ensure the test used is intended and labeled for that companion diagnostic purpose.

Tests inconsistent with FDA-approved companion diagnostic labeling for the intended agent may be denied.
When an FDA-approved companion diagnostic is available, use tests consistent with its labeling for therapy selection.

Documentation Required

ctDNA and Tissue Testing Have Complementary Roles

Because ctDNA (plasma) and tissue-based tests have appreciable false-negative rates, complementary testing should be used when clinically indicated. If tissue is available, tissue-based testing is generally preferred; plasma testing is an acceptable alternative when tissue is insufficient or biopsy is not feasible. Document rationale for test selection.

Both ctDNA and tissue testing have high specificity but appreciable false-negative rates — consider complementary testing to increase detection yield.
When tissue is available, tissue testing is recommended; plasma testing may be used when tissue is insufficient or biopsy is not feasible.
Document whether tissue was available and whether tissue-based testing or ctDNA was used, including rationale.

Denial Risk

Investigational Test Codes — Denial Risk

Investigational test codes listed in the coding section present a denial risk for the indicated investigational uses (examples include codes listed as investigational for geneTMB and certain cfDNA assays). Review the coding table carefully; use of these codes for investigational indications may result in claim denial.

Examples of investigational CPT/proprietary codes include 81404, 81405, 81479 and multiple proprietary cfDNA codes noted as investigational in the coding section.
Use of investigational-listed codes for the investigational indications may result in denial.

Step Therapy

No Step Therapy Requirements Specified

No explicit step therapy requirements or step-therapy protocols are described in these policy excerpts. Decisions about test sequencing should be guided by FDA labeling, NCCN/ASCO guidance, clinical context, and member benefits rather than by a step-therapy rule in this policy.

No step therapy listed in policy excerpts.
Tests should be ordered consistent with FDA-approved indications and guideline recommendations rather than a policy step-therapy requirement.

Documentation Required

Plasma Testing When Tissue Is Insufficient

Plasma (cfDNA) testing may be used when tissue is insufficient for standard molecular testing. When plasma is used as an alternative to tissue, document that tissue was insufficient and that follow-up tissue-based testing is planned if plasma testing does not identify a driver alteration.

Plasma testing is medically necessary when tissue is insufficient for standard molecular testing using formalin-fixed paraffin-embedded tissue and follow-up tissue-based analysis is planned if plasma testing is negative.
Document insufficiency of tissue for standard testing when ordering plasma assays.

Documentation Required

Documentation and Eligibility

Providers should document medical necessity, the clinical indication for testing, whether tumor tissue was available, which specimen type and test were used (tissue vs ctDNA), and the rationale for using plasma if chosen over tissue. Final coverage depends on the member's benefit.

Document medical necessity and specific clinical indication on the request and supporting records.
Document whether tumor tissue was available and whether tissue-based testing or ctDNA testing was used and why.
Final coverage determination is based on member benefit and documented medical necessity.

Documentation Required

Coverage Depends on Tissue Sufficiency Documentation

Coverage for tissue versus plasma testing depends on documentation of tissue sufficiency. Tissue-based tests are covered when medically necessary; plasma tests are covered when tissue is insufficient or when an FDA-approved plasma companion diagnostic is used consistent with labeling.

Tissue-based testing covered when medically necessary and documented.
Plasma/cell-free DNA testing covered when medically necessary or when tissue is insufficient and criteria are met.
When FDA-approved plasma companion diagnostics are used consistent with labeling, coverage may apply per member benefit.

Note

References Include Clinical Validation Studies and FDA Summaries

References include clinical validation studies and FDA summaries for cfDNA and liquid biopsy assays that support clinical utility and analytical performance. Providers may consult referenced literature and FDA Summary of Safety and Effectiveness Data documents for test performance details.

Clinical validation and utility studies are cited (see references) supporting use of cfDNA/liquid biopsy assays.
FDA SSED documents for FoundationOne Liquid CDx and Guardant360 CDx are included as references.

ctDNA / cell-free DNA definition

DefinitionCirculating tumor DNA (ctDNA) / cell-free DNA: Small fragments of DNA released into the blood from normal and tumor cells; most tumor-derived cfDNA arises from apoptotic and/or necrotic tumor cells and can be used for genomic tumor characterization.

SourceDerived from primary tumor, metastases, or circulating tumor cells; fragment length/integrity may reflect apoptotic vs necrotic origin.

Clinical useCan be assayed via plasma (liquid biopsy) to detect somatic tumor variants when tissue is unavailable or for longitudinal monitoring.

ctDNA definition (alternate)

DefinitionCirculating tumor DNA (ctDNA): Tumor-derived fragments of cell-free DNA circulating in the blood from apoptotic or necrotic tumor cells that can be used for genomic tumor profiling and mutation detection.

DistinctionctDNA is a subset of cell-free DNA (cfDNA) originating from tumor cells; assays must distinguish tumor-derived variants from background cfDNA.

Assay considerationsSensitivity depends on total cfDNA input, assay platform, and tumor shedding; negative ctDNA does not exclude a tumor variant when tissue is available.

NTRK detection methods definition

DefinitionNTRK detection methods: NTRK gene fusions can be detected by next-generation sequencing (NGS), reverse transcription–PCR (RT‑PCR) for known partners, fluorescence in situ hybridization (FISH) using break-apart probes, and immunohistochemistry (IHC) (generally research use); NGS is most comprehensive and tissue-sparing.

RT-PCR limitationRT-PCR detects only known translocation partners and cannot identify novel fusion breakpoints.

IHC and FISH rolesIHC has primarily research use; FISH can detect rearrangements that may generate fusion transcripts via break-apart probes.

Liquid biopsy / cfDNA assays definition

DefinitionLiquid biopsy / cfDNA assays: Plasma-based assays that detect circulating tumor DNA to identify actionable somatic alterations (eg, EGFR mutations, ALK/ROS1 fusions, KRAS mutations) for clinical decision-making and validated in clinical studies.

PlatformsIncludes targeted NGS panels, amplicon-based NGS, and droplet digital PCR (ddPCR) platforms used in clinical validation studies.

Clinical limitationAssay sensitivity varies with cfDNA input and tumor shedding; negative results may require follow-up tissue testing if clinically indicated.