Modifiedblue cross blue shield - kansasPolicy N/A

Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK)

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Defines use of somatic (tumor) biomarker testing—including tissue and circulating tumor DNA (liquid biopsy)—to identify EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, and NTRK alterations to guide targeted therapy in individuals with advanced or metastatic non-small-cell lung cancer (NSCLC). Applies to BCBSKS members and their providers.

Policy Summary

Payerblue cross blue shield - kansas

PolicySomatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in NSCLC (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK)

Policy CodePolicy N/A

Change TypeMAJOR — coding, nomenclature, and coverage updates

Effective DateJan 22, 2024

Last ReviewJan 22, 2025

Next Review DateN/A

Key ActionVerify member benefits and prior authorization requirements with BCBSKS before ordering somatic tissue or plasma ctDNA testing.

SourceLink

POLICY UPDATE CHANGES

Programmed death receptor 1 (PD-1) or its ligand (PD-L1) expression analysis may be considered medically necessary as a technique to predict treatment response to drug therapy.

Analysis of somatic variants of the KRAS gene terminology changed from 'mutations' to 'variants' and is considered experimental/investigational to predict non-response to anti-EGFR therapy.

Analysis for genetic alterations in RET, MET, and HER2 described as experimental/investigational; previous mentions of ROS and BRAF removed from that item.

Policy updated to align testing indications with FDA-approved companion diagnostics and NCCN recommendations; several new CPT and HCPCS codes added and others removed.

New medically necessary statements added for testing of EGFR exon 20 insertions, ALK in plasma, KRAS G12C in plasma, HER2 in tissue and plasma, and MET exon 14 skipping in plasma.

NTRK gene fusion testing (tissue and plasma ctDNA) was added as medically necessary to predict response to TRK inhibitor therapy in metastatic NSCLC.

Policy title updated to include NTRK.

Removed multiple sections related to HER2, PD‑L1 and other specific enumerated content; added RET inhibitor therapy mention and updated policy guidelines to exclude monoclonal antibody therapies such as amivantamab.

Coding updates: removed 0338U, added 0179U and later added 0478U; updated nomenclature for 81445 and 81455.

Policy guidance added: this policy does not address HER2 testing and does not address monoclonal antibody therapies such as amivantamab.

8genes addressed

FDA/NCCNFDA/NCCN-based approach

conditionalplasma testing stance

3 changescoding edits

NCCN v8.2025ctDNA guidance source

Coverage Criteria for Somatic Biomarker Testing

General coverage criteria for somatic biomarker testing

Covered when testing is used to select targeted therapy for individuals with advanced-stage or metastatic NSCLC being considered for targeted TKIs or TRK inhibitors.

Population and purpose: Individual has advanced-stage or metastatic non-small-cell lung cancer (stage III or IV) and is being considered for targeted therapy (eg, agents directed at EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, or NTRK).

Supported across policy statements specifying stage III/IV or advanced/metastatic NSCLC.

Specimen types: Somatic testing may be performed on tumor tissue biopsy specimens or circulating tumor DNA (ctDNA) from plasma (liquid biopsy) to guide targeted treatment selection, depending on gene-specific guidance and clinical circumstances.

Policy describes tissue and ctDNA as interventions of interest and allows ctDNA as an alternative in specified situations.

Covered when linked to FDA-approved targeted therapy indications

Coverage is tied to identifying actionable somatic alterations for which FDA-approved targeted therapies exist; companion diagnostic testing is referenced per drug indication.

Actionable biomarkers: Testing to identify EGFR, ALK, BRAF, ROS1, RET, MET exon 14 skipping, KRAS (including G12C), or NTRK alterations that are linked to FDA-approved targeted therapies is supported when the test and intended therapy will be used consistent with FDA labeling and any FDA-approved companion diagnostic is employed where specified.

Multiple FDA-approved drugs and companion diagnostics are enumerated in the regulatory status and targeted treatment tables.

EGFR (exons 18–21) tissue testing

Covered when ALL of the following are met for EGFR tissue testing:

EGFR tissue testing: Analysis of tumor tissue for somatic variants in EGFR exons 18–21 (examples: G719X, exon 19 deletions, L858R, T790M, S768I, L861Q) may be considered medically necessary to predict treatment response to an FDA‑approved EGFR therapy when the individual has advanced (stage III/IV) or metastatic NSCLC (eg, adenocarcinoma, large cell carcinoma, advanced squamous‑cell NSCLC, or NSCLC not otherwise specified), there are no FDA‑labeled contraindications to the requested agent, and the agent will be used consistent with the FDA label.

Policy lists exon 18–21 variants as covered in tissue; other uses are investigational.

EGFR exon 20 insertion testing

Covered when ALL of the following are met for EGFR exon 20 insertions:

EGFR exon 20 testing: Analysis of tumor tissue for EGFR exon 20 insertion mutations may be considered medically necessary to predict response to an FDA‑approved therapy for EGFR exon 20 insertions (eg, mobocertinib) when used consistent with the FDA label and no FDA‑labeled contraindications exist.

Specific exon 20 insertion testing in tissue is listed as medically necessary when label‑consistent.

EGFR plasma (diagnostic) testing

Covered when ALL of the following are met for EGFR plasma (ctDNA) testing at diagnosis:

EGFR plasma at diagnosis: Plasma analysis for somatic variants in EGFR exons 19–21 (examples: exon 19 deletions, L858R, T790M) using an FDA‑approved companion diagnostic plasma ctDNA test may be considered medically necessary as an alternative to tissue biopsy to predict response to FDA‑approved EGFR therapies when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

Policy specifies FDA‑approved plasma companion diagnostics may be used as an alternative to tissue at diagnosis.

EGFR T790M plasma testing at progression

Covered when ALL of the following are met for EGFR T790M at progression:

EGFR T790M plasma at progression: Plasma testing for the EGFR T790M resistance variant using an FDA‑approved companion diagnostic may be considered medically necessary to guide osimertinib when tissue biopsy to obtain new tissue is not feasible (eg, insufficient tissue, no biopsy‑amenable lesion, or unable to undergo biopsy), and when the agent will be used consistent with the FDA label and no FDA‑labeled contraindications exist.

Repeat testing at progression is supported to identify acquired resistance (T790M) as noted in rationale and repeat testing guidance.

ALK testing (tissue and plasma alternative)

Covered when ALL of the following are met for ALK testing:

ALK tissue testing: Analysis of tumor tissue for ALK rearrangement variants may be considered medically necessary to predict response to FDA‑approved ALK inhibitor therapy in individuals with advanced/metastatic NSCLC (eg, adenocarcinoma or when an adenocarcinoma component cannot be excluded), provided there are no FDA‑labeled contraindications and the agent will be used consistent with its FDA label.

ALK plasma testing: Plasma ctDNA analysis for ALK rearrangements using an FDA‑approved companion diagnostic may be considered medically necessary as an alternative to tissue when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

Policy allows FDA‑approved plasma companion diagnostic as tissue alternative for ALK.

BRAF V600E testing (tissue)

Covered when ALL of the following are met for BRAF V600E testing:

BRAF V600E tissue testing: Analysis of tumor tissue for the somatic BRAF V600E variant may be considered medically necessary to predict response to FDA‑approved BRAF and/or MEK inhibitor therapy (eg, dabrafenib plus trametinib) in individuals with advanced or stage III/IV NSCLC (eg, adenocarcinoma or when an adenocarcinoma component cannot be excluded) when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

Plasma BRAF testing is considered investigational per policy.

ROS1 testing (tissue)

Covered when ALL of the following are met for ROS1 testing:

ROS1 tissue testing: Analysis of tumor tissue for ROS1 rearrangements may be considered medically necessary to predict response to an FDA‑approved ROS1 inhibitor (eg, crizotinib) in individuals with advanced or stage III/IV NSCLC (eg, adenocarcinoma or when an adenocarcinoma component cannot be excluded) when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

Plasma ctDNA testing for ROS1 is considered investigational per policy.

KRAS testing (G12C)

Covered when ALL of the following are met for KRAS G12C testing:

KRAS G12C tissue testing: Analysis of tumor tissue for KRAS somatic variants (eg, G12C) may be considered medically necessary to predict response to FDA‑approved KRAS G12C inhibitors (eg, sotorasib, adagrasib) in individuals with advanced or stage III/IV NSCLC when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

KRAS G12C plasma testing: Plasma ctDNA testing for KRAS G12C using an FDA‑approved companion diagnostic may be considered medically necessary as an alternative to tissue biopsy to predict response to KRAS G12C inhibitors when both the agent and ctDNA test are used per FDA labeling and no FDA‑labeled contraindications exist.

Policy supports FDA‑approved plasma companion diagnostics for KRAS G12C as tissue alternative.

RET testing (tissue)

Covered when ALL of the following are met for RET testing:

RET tissue testing: Analysis of tumor tissue for RET somatic alterations (fusions) may be considered medically necessary to predict response to RET inhibitor therapy (eg, pralsetinib, selpercatinib) in individuals with metastatic or stage III/IV NSCLC when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

Plasma-based RET testing is considered investigational per policy.

MET exon 14 skipping testing

Covered when ALL of the following are met for MET exon 14 skipping testing:

MET exon 14 tissue testing: Analysis of tumor tissue for alterations that lead to MET exon 14 skipping may be considered medically necessary to predict response to MET inhibitor therapy (eg, capmatinib) in individuals with metastatic or stage III/IV NSCLC when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

MET exon 14 plasma testing: Plasma ctDNA testing for MET exon 14 skipping using an FDA‑approved companion diagnostic may be considered medically necessary as an alternative to tissue biopsy to predict response to MET inhibitors when used per FDA labeling and no FDA‑labeled contraindications exist.

Policy cites FoundationOne Liquid CDx as an example of plasma companion diagnostic for MET exon 14.

NTRK fusion testing (tissue and plasma alternative)

Covered when ALL of the following are met for NTRK fusion testing:

NTRK tissue testing: Analysis of tumor tissue for NTRK gene fusions may be considered medically necessary to predict response to TRK inhibitor therapy (eg, larotrectinib, entrectinib) in individuals with metastatic or stage III/IV NSCLC when used consistent with FDA labeling and no FDA‑labeled contraindications exist.

NTRK plasma testing: Plasma ctDNA testing for NTRK fusions using an FDA‑approved companion diagnostic may be considered medically necessary as an alternative to tissue biopsy to predict response to TRK inhibitors when used per FDA labeling and no FDA‑labeled contraindications exist.

Policy added NTRK tissue and plasma companion diagnostic coverage when label‑consistent.

Plasma testing when tissue is insufficient

Covered when ALL of the following are met for plasma testing when tissue is insufficient:

Plasma when tissue insufficient: Plasma testing for oncogenic driver variants that would be considered medically necessary on tissue may be considered medically necessary when: 1) the individual does not have sufficient tissue for standard molecular testing using formalin‑fixed paraffin‑embedded tissue; AND 2) follow‑up tissue‑based analysis is planned should no driver variant be identified via plasma testing.

Policy requires planned follow‑up tissue analysis if plasma testing is negative or non‑diagnostic.

Biomarker-specific coverage (tissue and plasma)

Covered when evidence includes FDA-approved therapeutics with NCCN recommendation of 2A or higher (per-biomarker statements in the document):

Tissue-based testing for listed biomarkers: For individuals with advanced or metastatic NSCLC being considered for targeted therapy, tissue‑based somatic testing for EGFR variants, ALK rearrangements, BRAF V600E, ROS1 rearrangements, RET fusions, MET exon 14 skipping, KRAS variants (including G12C), and NTRK fusions is supported by FDA approvals and NCCN recommendations (2A+) and may be considered medically necessary when used consistent with FDA labels.

Chunks summarize per‑biomarker regulatory/rationale support.

Plasma/ctDNA testing for listed biomarkers: For individuals with advanced/metastatic NSCLC being considered for targeted therapy, plasma ctDNA testing for select biomarkers (eg, EGFR, ALK, MET exon 14 skipping, KRAS G12C, NTRK) using FDA‑approved companion diagnostic plasma tests may be considered medically necessary as an alternative to tissue in situations described by the policy; for some biomarkers (eg, BRAF, ROS1, RET) plasma companion diagnostic approvals or evidence are lacking and plasma testing is considered investigational.

Policy lists biomarker‑specific plasma coverage and exceptions across chunks 60–65 and 61,63.

Appropriate use of plasma ctDNA

NCCN v8.2025 recommendations summarized in this policy (plasma ctDNA):

ctDNA usage constraints: Plasma ctDNA testing should not be used in lieu of a histologic tissue diagnosis; ctDNA is not routinely recommended for stages I–III (tissue preferred); ctDNA is primarily appropriate for advanced/metastatic disease and may be used to complement tissue testing to increase detection yield and shorten turnaround time.

NCCN guidance notes specificity is high but false‑negative rates warrant complementary tissue testing.

Interpretation and limitations

Performance and interpretation considerations:

Assay limitations to consider: ctDNA assays have high specificity but appreciable false‑negative rates; limitations include low tumor fraction/ctDNA (some assays report ctDNA fraction), potential detection of non‑tumor variants from clonal hematopoiesis (CHIP) or marrow clones (eg, KRAS, TP53), and variable analytic ability to detect fusions or complex genomic alterations; tissue testing limitations include low tumor percent and assay‑specific fusion detection limits. These limitations support complementary use of tissue and plasma testing.

Policy describes these interpretation and analytic constraints in NCCN summary.

Covered with criteria (gene- and test-specific summary)

Covered when ALL of the following are met (gene- and test-specific statements appear across the policy):

General tissue/plasma coverage logic: The test and intended targeted agent must be used consistently with their FDA‑approved labels; the individual has stage III or IV (unresectable or metastatic) NSCLC (eg, adenocarcinoma, large cell carcinoma, or NSCLC not otherwise specified); and there are no FDA‑labeled contraindications to the requested agent.

Policy emphasizes label‑consistent use and specified disease stage.

PD-L1 testing: PD‑L1 expression analysis of tissue may be considered medically necessary to predict treatment response to specified FDA‑approved immunotherapies when used consistent with FDA labels.

Policy added PD‑L1 statement as medically necessary in label‑consistent situations.

Specific somatic variant testing added as medically necessary: Testing for EGFR exon 20 insertions, ALK (including plasma), KRAS G12C in plasma, HER2 in tissue and plasma, and MET exon 14 skipping in plasma may be considered medically necessary to predict response to their respective FDA‑approved therapies when used per labels.

Policy updates added several gene/test‑specific medically necessary statements.

Not medically necessary / Experimental

Experimental / investigational — KRAS: Analysis of somatic variants of the KRAS gene is considered experimental / investigational when used to predict treatment non‑response to anti‑EGFR therapy (eg, predicting lack of benefit from EGFR TKIs or cetuximab) in NSCLC.

Policy retains KRAS‑to‑anti‑EGFR investigational language.

Experimental / investigational — RET, MET, HER2 (certain contexts): Analysis for genetic alterations in RET, MET, and HER2 is considered experimental / investigational in contexts outside the specific FDA‑labeled/covered situations detailed elsewhere in the policy.

Policy clarifies covered vs investigational contexts for these genes across sections.

Tumor mutational burden (TMB): Analysis of tumor mutational burden to predict treatment response to targeted therapy in patients with NSCLC is considered experimental / investigational.

TMB testing remains investigational for targeted therapy selection per policy.

Covered testing for predictive targeted therapy selection

Covered when ALL of the following are met

NTRK tissue testing: Analysis of tumor tissue for NTRK gene fusions may be considered medically necessary to predict treatment response to TRK inhibitor therapy (eg, larotrectinib or entrectinib) in individuals with metastatic or stage III/IV NSCLC when the agent will be used consistent with the FDA label and no FDA‑labeled contraindications exist.

NTRK added to policy title and covered indications per updates.

NTRK plasma ctDNA testing: Analysis of plasma for NTRK gene fusions using an FDA‑approved companion diagnostic ctDNA test may be considered medically necessary as an alternative to tissue biopsy to predict response to TRK inhibitor therapy in metastatic NSCLC when both the agent and ctDNA test will be used consistent with their FDA‑approved labels and no FDA‑labeled contraindications exist.

Policy specifies plasma companion diagnostic alternative for NTRK when label‑consistent.

Other listed genes (general rule): Analysis of tumor tissue or plasma ctDNA for listed somatic alterations (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS) may be considered medically necessary to predict treatment response to FDA‑approved therapies when the agent and test are used consistently with FDA labeling and no FDA‑labeled contraindications exist.

See gene‑specific sections for detailed criteria and exclusions.

No explicit exclusions are provided in the excerpted policy text. Coverage determinations are instead framed around specific gene- and test-level criteria, FDA‑approved companion diagnostic status, NCCN guideline recommendations, and member contract or benefit verification requirements; refer to the policy’s gene-specific statements and the member’s contract to determine whether a requested test meets medical necessity.

Monoclonal antibody therapies and testing related to those agents are not evaluated in the targeted treatment table and are explicitly excluded from this review; the policy also clarifies it does not address monoclonal antibody therapies such as amivantamab.

Many uses of tissue- or plasma-based testing are described as experimental/investigational when they fall outside the specific, labeled indications enumerated in the policy. Examples include plasma testing for some biomarkers (BRAF, ROS1, RET) and tissue or plasma analyses of certain variants when not meeting the gene‑ and label‑specific criteria.

The policy notes that no plasma tests have FDA approval as companion diagnostics to select individuals with NSCLC for ROS1- or RET-directed therapies; studies for these plasma companion-diagnostic indications were not identified in the review.

Per NCCN guidance incorporated into the policy, plasma ctDNA testing should not be used in lieu of a histologic tissue diagnosis. Tissue-based testing is preferred in stages I–III, and plasma testing is generally reserved for advanced/metastatic disease or when tissue is inadequate.

The policy was updated: prior broader statements about NTRK, PD‑L1, and HER2 were modified or removed and replaced with more label‑consistent, gene‑specific items. The document explicitly states that the policy does not address HER2 broadly and removes some prior enumerated sections for NTRK and PD‑L1 while adding other label‑consistent statements.

Outside the specific, label‑consistent contexts listed in the policy, all other uses of NTRK or HER2 analysis in tissue or plasma are considered investigational/experimental and are not covered.

Within the provided excerpt there are no explicit single-line ‘not medically necessary’ conditions listed; instead, the policy frames noncoverage through experimental/investigational designations for uses not meeting the specified criteria and by reference to member contract/benefit verification requirements.

The policy documents drug‑specific limitations for some agents (for example, historical limitations in the gefitinib label are noted) and indicates that test use and interpretation should be consistent with any FDA-labeled limitations for the targeted drug.

The policy specifies that analysis of the listed genes (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK) in tissue or plasma is considered experimental/investigational in situations that do not meet the detailed, gene‑ and specimen‑specific medical‑necessity criteria presented in the document.

Routine ctDNA testing outside of advanced/metastatic disease is not recommended. Plasma testing is supported mainly when tissue is insufficient or when an FDA‑approved plasma companion diagnostic exists; otherwise tissue testing is preferred for non‑advanced disease.

The policy explicitly states that routine use of ctDNA is not recommended in stages I–III and that tissue‑based testing is preferred in these earlier stages of disease.

Somatic analysis of HER2 (ERBB2) variants is considered investigational when requested for uses outside the specific, FDA‑labeled therapy indications; the policy notes removal of broader HER2 statements and focuses coverage on label‑consistent situations where applicable.

PD‑L1 testing is addressed in a limited, label‑consistent manner: tissue PD‑L1 expression analysis may be considered medically necessary when used to predict response to FDA‑approved immunotherapies per their labels; other PD‑L1 uses are designated investigational.

Indications Covered by This Policy

inv-88: Testing to identify EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, or NTRK alterations to guide selection of targeted therapies in individuals with advanced-stage or metastatic NSCLC.

Testing to identify EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, or NTRK alterations to guide selection of targeted therapies in individuals with advanced-stage or metastatic NSCLC.

Indication summary: Somatic testing (tissue or ctDNA as specified) to identify actionable alterations in EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, or NTRK for the purpose of selecting FDA‑approved targeted therapies in individuals with advanced‑stage or metastatic NSCLC is addressed by this policy.

Both tissue and ctDNA are included as interventions of interest per policy scope.

inv-89: Advanced/metastatic NSCLC with specific somatic alterations to identify candidates for FDA-approved targeted therapies

Advanced/metastatic NSCLC with specific somatic alterations (EGFR activating mutations, ALK rearrangements, BRAF V600E, ROS1, KRAS G12C, RET fusions, MET exon 14 skipping, NTRK fusions) to identify candidates for listed FDA-approved targeted therapies.

Drug‑linked testing: Testing is intended to identify specific somatic alterations (eg, EGFR sensitizing variants, ALK rearrangements, BRAF V600E, ROS1 fusions, KRAS G12C, RET fusions, MET exon 14 skipping, NTRK fusions) that are indications for FDA‑approved targeted therapies listed in the regulatory/targeted treatment tables.

Table entries and regulatory status link each biomarker to companion diagnostics and approved agents.

inv-90: Advanced or metastatic NSCLC when use of a targeted FDA-approved therapy is being considered and testing will be used consistent with the FDA-approved label.

Advanced or metastatic NSCLC when use of a targeted FDA-approved therapy is being considered and testing will be used consistent with the FDA-approved label.

Stage and label consistency: Patient has advanced or metastatic (stage III/IV) NSCLC and testing is ordered to inform use of a targeted FDA‑approved therapy; both the test and intended therapy will be used consistent with FDA labeling and there are no FDA‑labeled contraindications to the agent.

Gene‑ and specimen‑specific criteria (tissue vs plasma) are detailed elsewhere in the policy.

inv-91: Advanced or metastatic NSCLC patients being considered for targeted therapy when detection of actionable somatic alterations would inform treatment selection.

Advanced or metastatic NSCLC patients being considered for targeted therapy when detection of actionable somatic alterations would inform treatment selection.

Biomarkers to assess: Detectable actionable somatic alterations include EGFR (exon 19 deletions, L858R, exon 20 insertions, T790M at progression), ALK rearrangements, BRAF V600E, ROS1 rearrangements, RET fusions, MET exon 14 skipping, KRAS variants (including G12C), and NTRK fusions; tissue testing is broadly supported and ctDNA is supported for select biomarkers per FDA companion diagnostic availability and policy criteria.

Chunks 55–65 summarize evidence and FDA/NCCN support per biomarker.

inv-92: Analysis of specific somatic variants to predict treatment response in metastatic NSCLC.

Analysis of specific somatic variants to predict treatment response in metastatic NSCLC.

Specific variant analyses: Examples of specific somatic analyses considered in the policy include EGFR exon 19 deletions and exon 21 L858R, EGFR T790M at progression, ALK rearrangements, BRAF V600E, ROS1 rearrangements, and PD‑1/PD‑L1 expression for immunotherapy selection; these analyses inform assignment to FDA‑approved targeted agents or immunotherapies when used per labeling.

Policy historically and in updates cites these variant‑therapy links.

inv-93: Selection of FDA-approved targeted therapies or immunotherapies in patients with stage III/IV unresectable or metastatic NSCLC when tests and agents are used consistent with FDA labels.

Selection of FDA-approved targeted therapies or immunotherapies in patients with stage III/IV unresectable or metastatic NSCLC when tests and agents are used consistent with FDA labels (examples).

Label‑consistent selection: Testing to select FDA‑approved targeted therapies or immunotherapies (eg, EGFR TKIs for EGFR sensitizing variants, osimertinib for T790M, ALK inhibitors for ALK fusions, BRAF/MEK inhibitors for BRAF V600E, ROS1 inhibitors for ROS1 fusions, RET inhibitors for RET fusions, MET inhibitors for MET exon 14 skipping, KRAS G12C inhibitors for KRAS G12C, PD‑L1 testing for select immunotherapies) is considered medically necessary when tests and agents are used consistent with FDA labeling in stage III/IV disease and there are no FDA‑labeled contraindications.

See gene‑specific policy sections for specimen type and any plasma companion diagnostic conditions.

inv-94: Metastatic or unresectable NSCLC when testing will predict response to an FDA‑approved targeted therapy (including TRK inhibitors for NTRK fusions).

Metastatic or unresectable NSCLC when testing will predict response to an FDA‑approved targeted therapy (including TRK inhibitors for NTRK fusions) and both the drug and companion diagnostic will be used consistent with FDA labeling.

NTRK and other gene testing for therapy selection: In metastatic or unresectable NSCLC, testing for NTRK gene fusions and other listed somatic alterations is covered to predict response to FDA‑approved targeted therapies (eg, TRK inhibitors for NTRK fusions) when both the drug and any companion diagnostic are used consistent with FDA labeling.

NTRK was added to the policy title and coverage statements per coding updates.

Eligibility Requirements

ELIGIBILITY REQUIREMENTS: The excerpt does not list additional prior‑testing prerequisites as formal eligibility requirements. Clinical context (for example prior EGFR TKI exposure or suspected acquired resistance such as MET alterations or EGFR T790M) may inform when repeat or reflex testing is appropriate, but no discrete prior‑test gating rules are specified in the provided text.

ELIGIBILITY REQUIREMENTS: The policy notes MET alterations as a mechanism of acquired resistance in EGFR‑mutated adenocarcinomas, implying prior therapy history can be relevant to interpretation, but the excerpt provides no standalone prior‑authorization or prerequisite testing rules.

ELIGIBILITY REQUIREMENTS: Plasma testing as an alternative to tissue is supported when the individual lacks sufficient tissue for standard molecular testing and when follow‑up tissue testing is planned if plasma testing is negative; this context is part of the policy’s eligibility framework for plasma testing.

ELIGIBILITY REQUIREMENTS: Historical guideline context is provided (CAP/IASLC/AMP) indicating some biomarkers were not previously recommended as routine stand‑alone tests; however, the current policy emphasizes label‑consistent, advanced‑disease indications and does not add new formal eligibility gates in the excerpt.

ELIGIBILITY REQUIREMENTS: NCCN guidance incorporated into the policy supports ctDNA use primarily in advanced/metastatic disease and indicates tissue testing is preferred in stages I–III; this staging requirement effectively frames eligibility for routine plasma testing.

ELIGIBILITY REQUIREMENTS: The policy recognizes situations for concurrent tissue and liquid testing (for example, to enable longitudinal monitoring of variants such as EGFR T790M), but it does not impose explicit prior testing prerequisites beyond the clinical scenarios described.

ELIGIBILITY REQUIREMENTS: For requests involving expanded panel testing, the policy refers providers to the Comprehensive Genomic Profiling policy, which may have separate authorization or eligibility pathways.

Coding and Billing

Named companion diagnostics and assaysmixed

FoundationOne CDx	FDA-approved companion diagnostic (example listed for multiple drugs)
FoundationOne Liquid CDx	FDA-approved liquid biopsy companion diagnostic (example listed)
Guardant360 CDx	FDA-approved liquid biopsy companion diagnostic (example listed)
therascreen KRAS RGQ PCR kit	FDA-approved companion diagnostic for KRAS G12C (example listed)
cobas EGFR Mutation Test v2	FDA-approved companion diagnostic for EGFR (tissue or plasma)
Oncomine Dx Target Test	FDA-approved companion diagnostic for multiple biomarkers (example listed)
Ventana ALK (D5F3) CDx Assay	FDA-approved companion diagnostic for ALK
Vysis ALK Break Apart FISH Probe Kit	FDA-approved companion diagnostic for ALK (FISH)
Therascreen EGFR RGQ PCR kit / Rotor-Gene Q	FDA-approved EGFR companion diagnostic (examples)

Named FDA-approved plasma companion diagnosticmixedCovered

FoundationOne Liquid CDx

FDA-approved companion diagnostic (plasma) for entrectinib in NSCLC (named test)

Listed molecular and related procedure codesmixed

81191	NTRK1 translocation analysis
81192	NTRK2 translocation analysis
81193	NTRK3 translocation analysis
81194	NTRK 1/2/3 translocation analysis
81210	BRAF V600 variant(s) gene analysis
81235	EGFR gene analysis, common variants
81275	KRAS exon 2 variants (codons 12 and 13)
81276	KRAS additional variants (e.g., codon 61, 146)
81445	Solid organ neoplasm genomic sequence analysis panel 5-50 genes
81455	Solid organ or hematolymphoid neoplasm panel 51+ genes

1–10 of 24

1/3

Updated/Added CPT/HCPCS Codesmixed

81191	CPT code added (document provides list additions)
81192	CPT code added
81193	CPT code added
81194	CPT code added
81210	CPT code added
88364	CPT code added
88366	CPT code added
81445	CPT/seq panel code added/updated
81455	CPT/seq panel code added/updated
88341	CPT code added

1–10 of 14

1/2

Removed/Deleted Codesmixed

81406	Removed CPT code 81406
0338U	Removed
0397U	Deleted
0397U	Removed (duplicate reference)

Updated CPT/HCPCS/PLA codes referencedmixed

0338U	Removed (previously listed)
0179U	Added (coding update noted)
0478U	Added (effective 10-01-2024)
81445	Nomenclature updated (effective 01-01-2024)
81455	Nomenclature updated (effective 01-01-2024)

Liquid biopsy negative reflex — reflex to tissue when plasma negative for certain EGFR variants

ActionIf an FDA‑approved plasma EGFR companion diagnostic is negative for EGFR exon 19 deletions or L858R, reflex to tissue biopsy and routine tissue-based testing (FFPE) per the FDA label.

Applicable variantsEGFR exon 19 deletions and EGFR exon 21 L858R (sensitizing variants).

SettingAdvanced (stage III or IV) NSCLC workup when plasma ctDNA testing is used as an alternative to tissue testing.

RationalePlasma tests may miss these sensitizing EGFR variants (false negatives); tissue testing ensures detection per FDA guidance.

Reference tests mentionedExamples of intended-use plasma/tissue assays: cobas EGFR Mutation Test v2, Guardant360 CDx, OncoBEAM, InVisionFirst‑Lung.

Provider Actions and Documentation Requirements

Prior Authorization

Verify member benefits prior to testing

Verify member benefits with Blue Cross and Blue Shield of Kansas Customer Service before ordering testing; member contract language, state/federal mandates, and plan provisions take precedence and can affect coverage and prior authorization requirements.

Contact BCBSKS Customer Service to confirm coverage and any plan-specific prior authorization requirements.

Prior Authorization

No specific prior-authorization codes listed

The policy does not specify particular CPT/HCPCS codes that universally require prior authorization; providers should not assume code-level PA requirements are defined in this document.

Prior Authorization

Benefit verification required at time of service

Check the member's contract benefits at the time of service to determine coverage or noncoverage; prior authorization may be required per the member's benefits.

Member contract benefits determine applicability of coverage and any PA requirements.

Prior Authorization

Prior authorization considerations for FDA/NCCN-listed companion diagnostics

Tests linked to FDA-approved therapeutics with NCCN 2A+ recommendations are handled according to the pivotal evidence and companion diagnostic approvals; providers should document use of FDA‑approved companion diagnostics where applicable.

If an FDA‑approved companion diagnostic exists for the drug (see Table 2), document use of that test when ordering therapy.

Prior Authorization

Verify benefits and prior authorization before ordering

Medical necessity for listed molecular and plasma ctDNA tests is determined by the Policy section; verify member benefits and any prior authorization requirements with the plan prior to testing.

Ensure ordered testing is consistent with the Policy's medical‑necessity statements (gene, specimen type, and clinical context).

Documentation Required

Ensure label‑consistent use of tests and therapies

Use of tests and targeted agents must be consistent with FDA‑approved labels and intended clinical indications; document that the intended use aligns with FDA labeling to support coverage.

Testing and therapy intended for stage III/IV (unresectable or metastatic) disease should reflect FDA‑labeled indications and absence of FDA‑labeled contraindications.

Billing Rule

Update coding may affect prior authorization and billing

Coding changes have been made (codes added/removed and nomenclature updates) and may affect authorization and billing; confirm current CPT/HCPCS/PLA codes when submitting requests or claims.

Recent coding edits include removal of 0338U, addition of 0179U and 0478U, and nomenclature updates to 81445 and 81455; verify code applicability for authorization.

Note

Step Therapy

No step therapy requirements specified

No step therapy requirements are described in the policy excerpts; providers should refer to member benefits or drug‑specific coverage policies for any plan-level step therapy rules.

Note

Follow guideline‑based therapy sequencing

Guideline-based sequencing may apply: offer targeted therapies for identified driver alterations as initial or second‑line therapy per ASCO and other guideline recommendations; document prior therapies and rationale when relevant.

Follow ASCO guidance that targeted therapies for driver alterations may be offered as initial or second‑line therapy depending on prior treatment.
Document prior systemic therapy when ordering agents that require prior lines of therapy (e.g., adagrasib indication after at least one prior systemic therapy).

Note

Step Therapy

No explicit step therapy described in policy

The provided chunks do not describe explicit step therapy requirements; verify plan formularies and member benefits for any drug-specific step edits.

Prior Authorization

Route expanded panel requests to CGP policy

Refer providers to the Comprehensive Genomic Profiling policy for authorization pathways when ordering expanded panels (broad molecular profiling) rather than single‑gene companion diagnostics.

Expanded panel testing should follow the separate Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies policy for coverage/authorization rules.

Prior Authorization

Confirm member benefits with BCBSKS

Verify member benefits with BCBSKS Customer Service; plan‑specific provisions and state/federal mandates take precedence and can change coverage determinations.

Contact BCBSKS Customer Service to confirm coverage, prior authorization, and any exclusions before testing.

Documentation Required

Document use of FDA‑approved companion diagnostic

When a companion diagnostic is applicable, document the specific FDA‑approved companion diagnostic test used (e.g., Guardant360 CDx, FoundationOne CDx) and link results to the intended FDA‑approved therapy.

Include test name and result in the record when selecting an FDA‑approved targeted agent tied to a companion diagnostic (see Table 2).

Documentation Required

Document rationale and follow‑up plan for plasma testing

When ordering plasma (ctDNA) testing, document that tissue is insufficient for standard molecular testing or provide rationale for liquid biopsy, and plan for follow‑up tissue testing if plasma is negative.

Record why tissue is inadequate for testing and the plan for reflex tissue biopsy if plasma testing is negative.

Documentation Required

Document assay type and biomarkers tested

Document the assay type (broad molecular profiling vs specific assays) and the exact biomarkers/variants assessed in the report and medical record to support medical necessity.

Specify whether testing is a validated broad NGS panel or a single‑gene companion diagnostic and list biomarkers included (e.g., EGFR exons 18–21, KRAS G12C, NTRK fusions).

Documentation Required

Document clinical details when ordering plasma ctDNA

To support medical necessity for plasma ctDNA testing, document disease stage (advanced/metastatic), rationale for liquid biopsy (eg, insufficient tissue or need to shorten turnaround time), and assay limitations (ctDNA fraction, potential CHIP).

Record stage (III/IV), reason for choosing plasma over tissue, and any assay‑reported ctDNA fraction or known limitations.

Documentation Required

Document intent consistent with FDA labeling

When using plasma cfDNA tests, document that the test and any subsequent targeted therapy will be used consistently with FDA‑approved labels and include plans for tissue confirmation if required by FDA labeling.

Indicate intent to use test/agent per FDA label and plan for reflex to tissue testing if plasma negative for specified EGFR variants per FDA instructions.

Documentation Required

Ensure documentation demonstrates consistency with FDA labeling

Document that testing and intended targeted therapy will be used consistent with their FDA‑approved indications (eg, stage III/IV metastatic disease and absence of FDA‑labeled contraindications) to support coverage.

Include documentation tying the test result to an FDA‑approved therapy and that the patient's clinical status meets the labeled indication.

Denial Risk

Coverage contingent on member contract and mandates

Coverage is subject to member contract, state/federal mandates, and benefit verification; inclusion of codes in the Coding section does not imply individual member coverage or reimbursement.

Always check member contract benefits and any mandates before ordering or billing.

Denial Risk

No explicit denial triggers listed here

No explicit denial triggers are listed in the cited chunks; however, lack of adherence to the Policy's clinical criteria (eg, using ctDNA in lieu of tissue when not allowed) may result in denial.

Denial Risk

Conditions required for plasma testing reimbursement

Reimbursement for plasma ctDNA testing as an alternative to tissue is supported only when tissue-based testing is infeasible or when an FDA‑approved companion diagnostic plasma test is used; failure to meet these conditions may risk denial.

Plasma ctDNA testing should be used when tissue is insufficient or per an FDA‑approved plasma companion diagnostic; otherwise tissue testing is preferred.

Denial Risk

ctDNA not a substitute for histologic tissue diagnosis

Plasma ctDNA testing should not replace a histologic tissue diagnosis; ordering ctDNA in lieu of tissue diagnosis or in early‑stage disease (I–III) may not meet recommended practice and can risk noncoverage.

Billing Rule

Listing of codes does not imply coverage

Inclusion of a code in the Coding section does not guarantee coverage; confirm that the test meets the Policy criteria for medical necessity before billing to avoid denials.

Denial Risk

Reflex to tissue testing when plasma negative for EGFR sensitizing variants

If an FDA‑approved plasma companion diagnostic is negative for EGFR exon 19 deletions or L858R, reflex to tissue biopsy and testing per the FDA label; failure to perform reflex tissue testing when indicated may risk denial.

Follow FDA guidance that plasma-negative results for EGFR exon 19 or L858R should be reflexed to tissue testing.

Denial Risk

HER2 uses outside FDA‑approved labels are noncovered

Requests for somatic HER2 analysis in tissue or plasma outside FDA‑approved therapy indications are considered investigational and will be noncovered; document FDA‑label consistency to avoid denials.

Policy states all other uses of HER2 testing outside specified FDA indications are experimental/investigational and not covered.

Not Covered / Investigational Uses

NOT COVERED: In this excerpt there are no explicit test exclusions listed as blanket non‑covered items; noncoverage is instead defined by the policy’s experimental/investigational designations and by tests or uses that do not meet the specified gene‑ and label‑consistent criteria or member contract provisions.

NOT COVERED: Monoclonal antibody therapies and their associated testing are not evaluated in the targeted treatment table and therefore are not included in the policy’s summary of companion diagnostics and indications.

NOT COVERED: The policy designates many gene/specimen combinations as experimental/investigational when used outside the labeled contexts listed in the policy (examples: plasma testing for BRAF V600E, ROS1, and RET; tissue/plasma uses of certain variants not meeting the medical‑necessity criteria).

NOT COVERED: Plasma ctDNA testing as a companion diagnostic for ROS1 and RET‑directed therapies is not supported because no FDA‑approved plasma companion diagnostics for these indications were identified.

NOT COVERED: Some variant or gene analyses have historically been considered experimental/investigational in certain contexts (for example, use of KRAS analysis to predict anti‑EGFR nonresponse); the policy retains investigational designations for many such uses outside the specified medical‑necessity criteria.

NOT COVERED: Broad testing uses and certain somatic analyses (for example, some HER2 uses, KRAS somatic variant analysis to predict anti‑EGFR nonresponse, and other unspecified investigational applications) are considered investigational and not covered when they fall outside FDA‑labeled or policy‑listed indications.

NOT COVERED: HER2 testing uses in tissue or plasma requested for indications outside FDA‑approved therapy labels are designated investigational and not covered under the policy.

Background

BACKGROUND: Over half of patients with NSCLC present with advanced, often incurable disease; identifying oncogenic driver variants (eg, EGFR sensitizing variants such as exon 19 deletions and exon 21 L858R) permits molecular subtyping and selection of targeted therapies that can alter management compared with standard chemotherapy.

Definitions and Key Terms

EGFR sensitizing variants

DefinitionSomatic EGFR variants in the tyrosine kinase domain—notably small deletions in exon 19 and the exon 21 L858R substitution—associated with sensitivity to EGFR tyrosine kinase inhibitors (eg, afatinib, erlotinib, gefitinib).

ExamplesExon 19 deletions; exon 21 L858R (leucine to arginine at codon 858)

Clinical useDetection guides selection of FDA‑approved EGFR TKIs for advanced-stage (stage III/IV) NSCLC when used consistent with FDA labeling.

EGFR resistance variant (T790M)

DefinitionEGFR T790M — a secondary substitution of methionine for threonine at codon 790 in exon 20 associated with acquired resistance to first- and second-generation EGFR TKIs.

Clinical implicationDetection of T790M at progression can guide use of osimertinib when tissue biopsy is not feasible and an FDA‑approved plasma companion diagnostic is used per labeling.

ContextT790M commonly arises after initial response to EGFR TKIs and may warrant repeat genomic testing at progression.

ALK rearrangement (EML4-ALK)

DefinitionALK rearrangement (eg, EML4-ALK) — a chromosomal inversion/fusion producing a constitutively active ALK tyrosine kinase found in approximately 3%–6% of NSCLC patients.

DetectionDetected by tissue testing (FISH, IHC, or NGS) and, where FDA‑approved companion diagnostics exist, by plasma ctDNA assays as an alternative to tissue per labeling.

PopulationMore common in never-smokers or light ex‑smokers with adenocarcinoma histology.

RET definition

DefinitionRET — a proto-oncogene encoding a receptor tyrosine kinase; RET fusions occur in approximately 0.6%–2% of NSCLC and can be targetable alterations.

Clinical useDetection of RET fusions can identify candidates for FDA‑approved RET inhibitors when used consistent with labeling.

PrevalenceRET fusions occur in ~0.6%–2% of NSCLC (and 1.2%–2% of adenocarcinomas).

MET definition

DefinitionMET — alterations in the MET gene (including events causing MET exon 14 skipping) that can drive NSCLC and are a known mechanism of acquired resistance in EGFR‑mutated adenocarcinomas.

Clinical implicationMET exon 14 skipping alterations may predict response to FDA‑approved MET inhibitors when detected in tissue or, per labeling, by plasma ctDNA tests as an alternative.

Role in resistanceMET alterations are recognized contributors to acquired resistance to EGFR TKIs.

ctDNA / cell-free DNA

DefinitionctDNA / cell‑free DNA — small fragments of nucleic acids circulating in peripheral blood derived from normal and tumor cells; tumor‑derived cfDNA (ctDNA) enables noninvasive genomic characterization (liquid biopsy).

LimitationsHigh specificity but appreciable false‑negative rates; low tumor fraction and potential confounding by clonal hematopoiesis (CHIP) can impact sensitivity and interpretation.

Use casesAppropriate primarily for advanced/metastatic disease as an alternative to tissue when tissue is insufficient or when an FDA‑approved plasma companion diagnostic is available; should not replace histologic diagnosis.

NTRK fusion testing methods

MethodsNTRK fusion testing methods include next‑generation sequencing (most comprehensive), reverse transcription‑PCR (detects known partners), fluorescence in situ hybridization (break‑apart probes detect rearrangements), and immunohistochemistry (primarily research use).

StrengthsNGS can identify novel fusion partners and simultaneously assess many genes with minimal tissue requirement.

LimitationsRT‑PCR detects only known partners/breakpoints and cannot find novel fusions; IHC is largely investigational for NTRK detection.

Laboratory-developed test (LDT)

DefinitionLaboratory‑developed test (LDT) — an in‑house validated clinical laboratory assay that must meet CLIA high‑complexity requirements; FDA has not required premarket review for such tests to date.

Regulatory noteLDTs are subject to CLIA licensure for high‑complexity testing and local laboratory validation standards.

Use in policyBoth FDA‑approved platforms and LDTs are referenced as available options for biomarker testing; selection should follow validated laboratory methods and policy criteria.

Liquid biopsy / ctDNA testing definition

DefinitionLiquid biopsy / ctDNA testing — blood‑based assays that detect circulating tumor DNA in processed plasma to identify actionable somatic variants noninvasively.

PerformanceThese assays have high specificity but up to ~30% false‑negative rates in some settings; complementary tissue testing is recommended to improve detection yield and reduce turnaround time.

Appropriate useSupported primarily for advanced/metastatic NSCLC when tissue is insufficient or when an FDA‑approved plasma companion diagnostic is available; not a substitute for histologic diagnosis.

ctDNA (plasma cell-free/circulating tumor DNA)

DefinitionctDNA (plasma cell‑free/circulating tumor DNA) — tumor‑derived nucleic acids present in peripheral circulation, most commonly assayed from processed plasma, used for noninvasive somatic testing.

Analytic notesAssays may report ctDNA fraction to aid interpretation; low ctDNA fraction can suggest compromised sensitivity.

RoleUsed to detect somatic alterations to guide targeted therapy in advanced/metastatic NSCLC per FDA labeling and guideline recommendations.

Broad molecular profiling

DefinitionBroad molecular profiling — testing strategies (typically NGS‑based) that simultaneously assess multiple biomarkers (eg, ALK, EGFR, BRAF, MET exon 14, RET, ERBB2/HER2, KRAS, NTRK, ROS1) to minimize tissue use and detect actionable alterations.

Guideline supportNCCN recommends broad molecular profiling to minimize tissue use and identify multiple actionable biomarkers (NCCN v8.2025).

Clinical advantageEnables concurrent assessment of multiple targets and emerging biomarkers, potentially improving speed and comprehensiveness of treatment selection.

ctDNA / plasma cell-free DNA (duplicate concept)

DefinitionctDNA / plasma cell‑free DNA — tumor‑derived nucleic acids measured in peripheral blood (processed plasma) used to detect somatic alterations as a liquid biopsy approach.

InterpretationBecause ctDNA originates from multiple sources, results must be interpreted in clinical context and may require tissue confirmation for negative plasma tests when actionable variants are suspected.

Use casesAppropriate for advanced/metastatic disease and when tissue is unavailable; not recommended as routine testing in stages I–III.

CHIP (clonal hematopoiesis) definition

DefinitionCHIP (clonal hematopoiesis of indeterminate potential) — a source of non‑tumor somatic mutations (eg, KRAS, TP53) detectable in plasma that can confound ctDNA results.

ImpactMutations from CHIP may be mistaken for tumor‑derived variants, affecting specificity of interpretation for liquid biopsy results.

ConsiderationLabs and clinicians should consider CHIP and corroborate plasma findings with clinical context and tissue testing when indicated.

Liquid biopsy / ctDNA (alternate chunk references)

DefinitionLiquid biopsy / ctDNA — blood‑based testing assessing circulating tumor DNA to identify actionable somatic variants; has high specificity but appreciable false‑negative rates (up to ~30%), supporting complementary tissue testing.

RecommendationConcurrent or reflex tissue testing is often recommended to confirm negative plasma results for actionable variants that would change management.

LimitationsLow tumor fraction, assay detection limits for fusions, and non‑tumor sources of mutation (eg, CHIP) are key limitations to consider.

Stage III/IV NSCLC definition used in coverage statements

DefinitionStage III/IV NSCLC — advanced non‑small‑cell lung cancer (stage III or IV) specified as the population for many covered somatic biomarker tests to predict treatment response to FDA‑approved targeted therapies.

ApplicabilityCoverage statements frequently require stage III or IV (unresectable or metastatic) disease and histologic subtypes adenocarcinoma, large cell carcinoma, or NSCLC not otherwise specified.

Policy basisPolicy revisions replaced the term 'metastatic' with 'stage III or IV' in multiple gene‑specific sections to align coverage population definitions.

NTRK gene fusion testing definition (added)

DefinitionNTRK gene fusion testing — analysis of tumor tissue (or plasma ctDNA when an FDA‑approved companion diagnostic is available) for NTRK1/2/3 gene fusions to predict response to TRK inhibitors (larotrectinib, entrectinib) in metastatic NSCLC when used consistent with FDA labeling.

MethodsNGS (most comprehensive), RT‑PCR (limited to known partners), FISH (break‑apart probes), and IHC (primarily research) can be used to detect NTRK fusions.

Policy updateNTRK was added to the policy title and coverage statements (posted 12‑23‑2024, effective 01‑22‑2025) as medically necessary in label‑consistent metastatic NSCLC situations.

ctDNA plasma testing as alternative when FDA-approved companion diagnostic available

StatementWhen an FDA‑approved plasma companion diagnostic exists for a given genomic alteration (eg, certain EGFR or other labeled tests), plasma ctDNA testing may be used as an alternative to tissue biopsy if used consistent with the FDA‑approved companion diagnostic labeling.

LimitationIf a plasma companion diagnostic is negative for specific actionable EGFR sensitizing variants (exon 19 deletions or L858R), reflex to tissue testing is required per FDA labeling.

ContextPlasma ctDNA testing is not a substitute for histologic tissue diagnosis and is primarily intended for advanced/metastatic disease; guideline recommendations (NCCN) support complementary use of tissue and plasma testing.

Provider / Billing Quick Actions

Step Therapy

Therapy sequencing per guidelines (quick action)

Therapy sequencing guidance: offer targeted therapy for identified driver alterations as initial or second-line therapy per ASCO and other guideline recommendations; document sequencing rationale in the medical record.

Prior Authorization

Expanded panel routing — see Comprehensive Genomic Profiling policy

For expanded panel testing or comprehensive genomic profiling, refer authorization and coverage questions to the separate Comprehensive Genomic Profiling policy as directed in Policy Guidelines.

Billing Rule

Reflex to tissue when plasma negative — operational guidance

Operationally, if an FDA‑approved plasma test for EGFR (exon 19 deletions or L858R) is negative, reflex to tissue biopsy and testing per FDA label to avoid false‑negative plasma results impacting therapy decisions.

Denial Risk

Conditions for plasma testing reimbursement (summary)

Summary — plasma testing reimbursement is contingent on meeting policy conditions: use in advanced/metastatic disease, insufficient tissue for standard testing, use of FDA‑approved companion diagnostics where applicable, and documentation/plan for reflex to tissue if negative.

Revision History and Policy Changes

2025-01-22policy_revisionLatest

Added PD-1/PD-L1 (Programmed death receptor 1 or its ligand) expression analysis as a medically necessary technique to predict treatment response; updated policy guidelines and rationale.

2024-01-01nomenclature_update

Updated nomenclature from 'mutations' to 'variants' in coding and policy language for several items.

2024-01-22coding_update

Extensive coding updates made including additions and removals of CPT/HCPCS codes and incorporation of liquid biopsy content; coding nomenclature updates applied.

CODING AND NOMENCLATURE UPDATES: The policy documents multiple coding and nomenclature changes — for example, replacing the word “mutations” with “variants” in several sections, adding and removing CPT/HCPCS and Proprietary Laboratory codes (eg, removal of 0338U, addition of 0179U and 0478U), and updating nomenclature for panel codes such as 81445 and 81455. These revisions may affect billing and prior‑authorization processes.

LABEL‑CONSISTENT USE REQUIRED: The policy repeatedly emphasizes that tests and targeted agents must be used consistent with their FDA‑approved labels; several effective dates and coding posts are noted (for example, coding updates effective 01‑01‑2024, additions effective 10‑01‑2024, and policy effective date 01‑22‑2025), and providers should confirm coding and labeling before ordering or billing.

Policy Summary

Payerblue cross blue shield - kansas

PolicySomatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in NSCLC (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, NTRK)

Policy CodePolicy N/A

Change TypeMAJOR — coding, nomenclature, and coverage updates

Effective DateJan 22, 2024

Last ReviewJan 22, 2025

Next Review DateN/A

Key ActionVerify member benefits and prior authorization requirements with BCBSKS before ordering somatic tissue or plasma ctDNA testing.

SourceLink

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