ModifiedUnitedHealthcarePolicy CS373NM.C

FDA Cleared or Approved Companion Diagnostic Testing (for New Mexico Only)

Policy governs coverage of FDA cleared or approved molecular oncology companion diagnostic tests (tissue and liquid biopsy) for members in New Mexico when used to inform targeted oncology therapy selection.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing (for New Mexico Only)

Policy CodePolicy CS373NM.C

Change TypeScope clarifiedtests and indication/drug pairings added

Effective DateMar 1, 2026

Next Review DateN/A

Key ActionDocument medical necessity in the patient's record, including test name, specimen type, and clinical context, when ordering FDA-cleared or approved CDx testing.

SourceLink

POLICY UPDATE CHANGES

Revised language to indicate this policy applies to tests that have been granted approval as FDA cleared or approved Companion Diagnostic (CDx) tests.

Added specific FDA-cleared/approved CDx tests and mapped proven medically necessary indication/drug pairings (e.g., FoundationOne CDx, Guardant360 CDx, MI Cancer Seek, Oncomine Dx Express/Target, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx).

Added medical records documentation requirements for coverage review and definition updates including 'Concurrent Testing'.

Added CPT codes 0211U and 0523U to applicable codes and removed several older CPT codes.

311genes assayed (FoundationOne Liquid CDx)

95%+

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analytic/clinical reproducibility (FoundationOne CDx)

≥10 mut/MbTMB cutpoint

2concurrent tissue+liquid allowed (stage IV)

≥1new CPT codes added

Coverage Criteria

inv-01: Covered CDx Uses

Covered when ALL of the following are met:

Primary coverage criteria: Test is an FDA cleared or approved Companion Diagnostic (CDx) listed in the FDA Cleared or Approved Companion Diagnostic Devices Table or has an FDA approval order designating it as an FDA cleared or approved CDx for the intended targeted therapeutic product and clinical indication, and the assay detects alterations in five or more genes in tumor tissue or liquid biopsy; and test results will be used to inform use of a targeted oncology therapeutic for the individual with the corresponding clinical indication.

Applies to listed tests and other FDA cleared/approved CDx tests meeting these conditions.

Named CDx tests with specific indication/drug pairings: Named FDA-cleared/approved CDx assays (for example: FoundationOne CDx, FoundationOne Liquid CDx, Guardant360 CDx, MI Cancer Seek, Oncomine Dx Express/Target, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx) are considered proven and medically necessary when used to inform management for their enumerated cancer indication/drug pairings as listed in the policy.

See policy lists and policy history for exact mapping of test to indication/drug pairings.

Subsequent use of an FDA cleared or approved CDx test on a new specimen for therapy selection is covered when the CDx criteria are met and the individual is experiencing disease recurrence or the cancer has progressed or did not respond to the most recent systemic therapy.

Applies to repeat testing on a new specimen when clinically indicated by recurrence, progression, or lack of response.

Concurrent testing: Concurrent tissue-based CDx and liquid biopsy-based CDx for the same clinical indication within 30 days is covered for advanced or metastatic (stage IV) breast cancer and advanced or metastatic (stage IV) non-small cell lung cancer when the CDx criteria are met.30 days

Concurrent Testing definition and cancer-type limitations are in the policy.

inv-02: Unproven or Not Medically Necessary Uses

Other uses: All other uses of FDA cleared or approved CDx tests not supported by adequate evidence or not meeting the policy-specified criteria are unproven and not medically necessary.

Uses and indication/drug pairings not listed in the policy or lacking evidence are considered unproven and not medically necessary.

inv-03: Guideline-linked coverage contexts

Covered when testing is an FDA-approved or validated NGS-based assay and used to guide selection of targeted therapy in the following tumor contexts as recommended by NCCN or other professional guidelines:

Guideline-recommended tumor-specific testing: Testing recommended as an option by NCCN, ASCO, IASLC or other professional guidelines for the listed tumor contexts (examples include: ampullary adenocarcinoma; bone cancers; cervical cancer; cutaneous melanoma BRAF testing; neuroendocrine/adrenal tumors for MSI/MMR/TMB; NSCLC biomarker panels; occult primary for TMB; ovarian/fallopian tube/primary peritoneal cancers for PARP inhibitor-associated testing; pancreatic adenocarcinoma for fusions, mutations, MSI/TMB).

Each tumor-specific recommendation references guideline options for FDA-approved and/or validated NGS assays or ctDNA platforms.

inv-04: Covered CDx testing

Covered when BOTH of the following are met for an FDA-cleared or approved CDx test:

CDx authorization and intended use: The test has been granted approval as an FDA-cleared or approved Companion Diagnostic (CDx) for the intended targeted therapeutic product and clinical indication OR appears in the FDA Cleared or Approved Companion Diagnostic Devices Table for that intended use.

Supports FDA-listed CDx tests and those with approval orders in the FDA PMA database.

Listed proven/medically necessary tests: Specific FDA-cleared/approved CDx assays named in the policy (for example FoundationOne CDx, FoundationOne Liquid CDx, Guardant360 CDx, MI Cancer Seek, Oncomine Dx Express/Test, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx) are proven and medically necessary when used to inform management for their enumerated indication/drug pairings.

See policy history for the full list of test-to-drug pairings.

Subsequent testing and specimen rules: Subsequent use of an FDA-cleared or approved CDx test on a new specimen is covered when the CDx criteria are met and the patient has disease recurrence or progression or did not respond to the most recent systemic therapy.

FDA-cleared or approved companion diagnostic (CDx) tests are covered only for the specific indication/drug pairings listed in this policy or when the test meets the policy’s CDx criteria. Uses of an FDA-cleared or approved CDx test for indication/drug pairings not listed in the policy are considered unproven and not medically necessary unless the test both will be used to inform a targeted oncology therapeutic decision for the individual and appears in the FDA Cleared or Approved Companion Diagnostic Devices Table or has an FDA Premarket Approval order designating it as a CDx for that intended use.

Current evidence does not establish that circulating cell-free DNA (cfDNA) testing can universally replace tissue biopsy for comprehensive genomic profiling. Assessment reports and included studies were judged to be of low to very poor quality and did not conclusively show that cfDNA-based testing leads to better clinical outcomes compared with tissue-based testing, nor that cfDNA can substitute for tissue biopsy across indications.

Single-modality testing (tissue-only or ctDNA-only) may miss actionable variants that would be detected by concurrent testing. Observational data show that concurrent tissue and ctDNA profiling can identify additional actionable findings beyond tissue alone (for example, ctDNA-unique ESR1 variants in breast cancer), and limitations of single-modality approaches (including low ctDNA tumor fraction and assay discordance) may reduce detection sensitivity and clinical utility.

Any use of an FDA-cleared or approved CDx test that does not meet the policy’s stated coverage criteria or that is outside the listed indication/drug pairings is considered unproven and not medically necessary. Coverage is limited to tests and uses explicitly supported by the policy criteria, the FDA CDx listing, or an FDA approval order for the intended therapeutic pairing.

Because evidence is insufficient for unlisted uses, all other applications of the FDA-cleared or approved CDx tests described in this policy are classified as unproven and not medically necessary. Providers should confirm that the specific test and indication are enumerated in the policy or the FDA CDx resources before ordering for coverage purposes.

Uses of FDA-cleared or approved CDx tests beyond the policy’s specified criteria and the listed indication/drug pairings are considered unproven and not medically necessary. Coverage is restricted to the situations defined by the policy’s CDx criteria, the FDA Cleared or Approved Companion Diagnostic Devices Table, or an FDA approval order specifying the CDx intended use.

Covered Indications and Test-to-Drug Pairings

inv-41: Specific cancer types and drug pairings listed per named CDx test (e.g., FoundationOne CDx for multiple tumor types and associated targeted therapies).

Test-specific covered indications: Use of a named FDA-cleared/approved CDx test to inform management for its listed cancer indication/drug pairing (examples in policy: FoundationOne CDx and FoundationOne Liquid CDx, Guardant360 CDx, MI Cancer Seek, Oncomine Dx Express/Target, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx).

Refer to the policy lists for exact test-to-drug pairings and cancer-specific indications.

inv-42: Advanced or recurrent solid tumors where identification of actionable genomic alterations may inform targeted therapy or immunotherapy decisions; tests used as companion diagnostics per FDA cleared indications.

Advanced or recurrent solid tumors: Testing is indicated for advanced or recurrent solid tumors when identification of actionable genomic alterations (including TMB, MSI, specific driver gene variants such as KRAS p.G12C, BRCA, ESR1, PIK3CA, and other alterations) may inform selection of targeted therapy or immunotherapy; use FDA-cleared companion diagnostics as indicated by assay labeling and guideline recommendations.

Provider Actions and Operational Guidance

Billing Rule

Applicable codes and potential prior authorization

Applicable procedure and diagnosis codes listed in this policy are provided for reference only and do not guarantee coverage or payment. Listing a code does not imply the service is covered. Benefit coverage and prior authorization (PA) requirements are determined by federal, state, or contractual requirements and applicable laws. Verify member benefit details and PA rules before ordering testing.

CPT codes added in most recent revision include 0211U and 0523U; previously removed codes include 0179U, 81445, 81449, 81450, 81451, 81455, 81456, and 81599. Confirm current applicable coding with payer billing resources.

Prior Authorization

Prior authorization — align with CDx intended use

Prior authorization may be required and, when requested, must align with the companion diagnostic’s FDA-cleared intended use and labeling. Order tests consistent with the CDx indication (tumor type, line of therapy, and specimen type) described in FDA labeling and this policy.

Coding and Billing

Applicable CPT/HCPCS Molecular Pathology Codesmixed

0022U	Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence or absence of variants and associated therapy(ies) to consider.
0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden.
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
0239U	Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free DNA, analysis of 311 or more genes, interrogation for sequence variants, including substitutions, insertions, deletions, select rearrangements, and copy number variations.
0242U	Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free circulating DNA analysis of 55-74 genes, interrogation for sequence variants, gene copy number amplifications, and gene rearrangements.
0473U	Oncology (solid tumor), next-generation sequencing (NGS) of DNA from formalin-fixed paraffin- embedded (FFPE) tissue with comparative sequence analysis from a matched normal specimen (blood or saliva), 648 genes, interrogation for sequence variants, insertion and deletion alterations, copy number variants, rearrangements, microsatellite instability, and tumor-mutation burden.
0523U	Oncology (solid tumor), DNA, qualitative, next-generation sequencing (NGS) of single-nucleotide variants (SNV) and insertion/deletions in 22 genes utilizing formalin-fixed paraffin-embedded tissue, reported as presence or absence of mutation(s), location of mutation(s), nucleotide change, and amino acid change.
0543U	Oncology (solid tumor), next-generation sequencing of DNA from formalin-fixed paraffin-embedded (FFPE) tissue of 517 genes, interrogation for single-nucleotide variants, multi-nucleotide variants, insertions and deletions from DNA, fusions in 24 genes and splice variants in 1 gene from RNA, and tumor mutation burden.
81479	Unlisted molecular pathology procedure

Applicable CPT codes addedCPT

0211U	CPT code added to applicable codes
0523U	CPT code added to applicable codes

Applicable CPT codes removedCPT

0179U	CPT code removed from applicable codes
81445	CPT code removed from applicable codes
81449	CPT code removed from applicable codes
81450	CPT code removed from applicable codes
81451	CPT code removed from applicable codes
81455	CPT code removed from applicable codes
81456	CPT code removed from applicable codes
81599	CPT code removed from applicable codes

Tumor mutational burden (TMB) — key metric

DefinitionTumor mutational burden (TMB) is a measure of somatic mutations per megabase reported by some comprehensive genomic profiling assays, used as a predictive biomarker for immunotherapy response.

Key cutpoint used for CDx pembrolizumab approvalTMB ≥ 10 mut/Mb (approved CDx cutpoint used with FoundationOne CDx for pembrolizumab in TMB-high solid tumors).

Clinical context for useTMB-high designation in trials (e.g., KEYNOTE-158) identified individuals with higher response rates to pembrolizumab after prior therapy and with no satisfactory alternative treatments.

TMB-high threshold

Assay-specific threshold exampleTMB-high defined as ≥ 10 mut/Mb when determined by the FoundationOne CDx assay (used in pembrolizumab approval).

Ordering Requirements

Documentation Required

Ordering requirement: document medical necessity in chart

Ordering clinicians must document medical necessity in the patient's medical record when requesting CDx testing; no explicit restriction on who may order is stated in this policy portion.

Ensure documentation includes the clinical reasons and how results will inform targeted therapy selection.
Maintain legible records and make them available upon request for coverage review.

Documentation Required

Ordering: consider stage, prior therapy, and tissue availability

When ordering CDx testing, consider clinical stage (advanced/metastatic), prior therapies, and tissue availability; simultaneous tissue and liquid testing may be relevant depending on clinical circumstances.

Policy supports concurrent tissue and liquid CDx testing in select stage IV cancers and studies suggest combined testing can reduce time to diagnosis.
Document clinical stage and prior treatments on the order to support medical necessity.

Frequency and Re-testing Limits

FDA cleared or approved CDx tests (new specimen) — Subsequent use permitted

Policy stanceSubsequent use of an FDA cleared or approved CDx test on a new specimen is considered proven and medically necessary when criteria are met (e.g., disease recurrence or progression or lack of response to most recent systemic therapy).

Baseline conditionThe CDx test must meet policy criteria (FDA-cleared/approved CDx status and intended-use alignment).

Examples referencedFoundationOne Liquid CDx is listed as proven and medically necessary for specific indication/drug pairings; same subsequent-use rule applies to other FDA-cleared/approved CDx tests meeting criteria.

FoundationOne Liquid CDx / Guardant360 CDx — Frequency guidance

Frequency limits statedNo explicit frequency limits are stated for FoundationOne Liquid CDx or Guardant360 CDx in this policy portion.

Not Covered / Unproven Uses

Uses and indications that are not listed in this policy or that lack adequate supporting evidence are considered unproven and not medically necessary. Coverage is applicable only when the CDx criteria in the policy are met and the test is being used to guide a targeted oncology therapeutic decision consistent with FDA-listed indications or an FDA approval order.

The policy does not support routine replacement of tissue-based comprehensive genomic profiling (CGP) with liquid biopsy (cfDNA) in all situations. Independent assessments have found the quality of available studies to be poor, and current data do not conclusively demonstrate that cfDNA testing alone provides equivalent or superior clinical outcomes to tissue-based testing for all indications.

This portion of the document does not list any specific test types or clinical indications that are categorically excluded beyond the general unproven/not medically necessary statements; rather, limitations and uncertainty about single-modality approaches and evidence gaps are noted and used to guide coverage decisions.

All uses of FDA-cleared or approved CDx tests that do not meet the policy criteria or that fall outside the listed indication/drug pairings are unproven and not medically necessary. Providers should verify the test’s CDx status and the specific intended therapeutic pairing against the policy and FDA resources before proceeding.

Background

A companion diagnostic (CDx) is a test that provides information essential for the safe and effective use of a corresponding therapeutic product. This policy applies to FDA-cleared or approved CDx tests intended to detect genomic alterations in tumor tissue or circulating tumor DNA and to inform selection of targeted oncology therapies when used in accordance with the test’s approved indication and the policy’s coverage criteria.

Definitions

Companion Diagnostic — definition and FDA relation

DefinitionCompanion Diagnostic (CDx): a tool that provides information essential for the safe and effective use of a corresponding therapeutic drug; in this policy, an FDA-cleared or approved test for use with a specific drug or group of drugs.

Relation to FDA listsA CDx is eligible to be listed in the FDA’s Cleared or Approved Companion Diagnostic Devices table or identified via an FDA PMA approval order for a specific intended use.

Policy implicationCoverage applies only to tests that have been granted approval as FDA-cleared or approved Companion Diagnostics and meet the intended-use pairing requirements.

Liquid Biopsy — definition and specimen considerations

DefinitionLiquid Biopsy: testing performed on a sample of bodily fluid to identify tumor-derived cells or circulating tumor DNA/RNA (cfDNA/ctDNA) used to detect genomic alterations.

Revision History

2026-03-01scope_updateLatest

Policy scope narrowed to apply specifically to tests granted approval as FDA cleared or approved Companion Diagnostic (CDx) tests; FoundationOne CDx explicitly listed as proven and medically necessary for specified indication/drug pairings.

tests_added

Multiple FDA-cleared/approved CDx assays (including Guardant360 CDx, MI Cancer Seek, Oncomine Dx Express Test, Oncomine Dx Target Test, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx, and others) and numerous indication/drug pairings were added to the policy history as proven and medically necessary.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing (for New Mexico Only)

Policy CodePolicy CS373NM.C

Change TypeScope clarifiedtests and indication/drug pairings added

Effective DateMar 1, 2026

Next Review DateN/A

Key ActionDocument medical necessity in the patient's record, including test name, specimen type, and clinical context, when ordering FDA-cleared or approved CDx testing.

SourceLink

On This Page

Applies to clinically indicated repeat testing.

Concurrent tissue and liquid CDx testing: Concurrent testing using an FDA-cleared/approved tissue-based CDx and a liquid biopsy-based CDx is covered for advanced or metastatic (stage IV) breast cancer and advanced or metastatic (stage IV) NSCLC when CDx criteria are met.

Policy explicitly allows concurrent tissue+liquid CDx in these specific cancer types.

Assay content (e.g., number of genes: FoundationOne Liquid CDx = 311 genes; Guardant360 CDx = 55 genes; MI Cancer Seek = 228 genes) defines reported biomarkers.

inv-43: Locally advanced or metastatic ampullary adenocarcinoma and pancreatic adenocarcinoma: testing for actionable somatic findings via FDA-approved/validated NGS assay.

Ampullary and pancreatic adenocarcinoma: For locally advanced or metastatic ampullary adenocarcinoma and pancreatic adenocarcinoma, testing for actionable somatic findings (fusions, mutations, amplifications, MSI/MMR deficiency, and TMB) via an FDA-approved and/or validated NGS-based assay is recommended as an option to guide anticancer therapy.

Recommendation sourced from NCCN guideline options.

inv-44: Various other cancers — guideline-recommended options to use FDA-approved/validated NGS assays or ctDNA.

Other guideline-recommended cancers: For tumor types such as metastatic bone cancers (chondrosarcoma, chordoma, Ewing sarcoma, osteosarcoma), cervical cancer, cutaneous melanoma (BRAF), neuroendocrine/adrenal tumors (MSI/MMR/TMB), occult primary (TMB), and ovarian/fallopian tube/primary peritoneal cancer (PARP-related testing), use of FDA-approved or validated NGS assays or validated ctDNA platforms is a guideline-recommended option to guide therapy selection.

Specific testing targets and contexts are described in NCCN and other guideline references.

inv-45: Multiple solid tumor types where FDA-approved or validated assays are recommended by NCCN to identify actionable alterations for targeted therapies.

Multiple solid tumor types per NCCN: For multiple solid tumor types including ovarian, fallopian tube, primary peritoneal, pancreatic adenocarcinoma, uterine neoplasms, vaginal cancer, and vulvar cancer, NCCN recommends FDA-approved or validated assays as an option to identify actionable alterations (e.g., BRCA, MSI, NTRK, TMB, fusion genes) to guide targeted therapies.

Recommendations cite NCCN guideline categories and testing targets.

PA should reflect the CDx intended use for the specific advanced solid tumor and therapy selection.
For molecular oncology tests that are not FDA-cleared/approved as CDx, follow the Molecular Oncology Testing policy referenced in this document.

Prior Authorization

Verify benefit and authorization rules

Before ordering testing, verify the member’s benefit plan and any contractual or state-specific authorization requirements. Federal, state, or contractual terms may override the policy; always follow plan-specific rules.

Check for plan-specific PA portals, prior authorization forms, or required precertification numbers.
Confirm whether concurrent testing or repeat CDx testing on a new specimen requires separate authorization per contract.

Denial Risk

Limitations of single-modality testing

Single-modality testing (tissue-only or ctDNA-only) can miss actionable variants that the alternate modality might detect. Use concurrent or reflex testing strategies when clinically indicated to optimize detection of guideline-relevant alterations.

Concurrent tissue and liquid CDx testing is considered proven and medically necessary for advanced/metastatic (stage IV) breast cancer and stage IV NSCLC when criteria are met.
When ctDNA tumor fraction (TF) is low (e.g., <1%), sensitivity of liquid biopsy decreases and reflex tissue biopsy should be considered.
Relying solely on one modality may lead to denial risk if another modality would identify additional actionable variants relevant to treatment selection.

Documentation Required

Medical record requirements

The patient’s medical record must contain documentation that fully supports the medical necessity for the requested test. Medical records may be requested for review and lack of adequate documentation can lead to denial or noncoverage.

Include relevant medical history, physical examination findings, prior treatments and responses, and diagnostic test results.
Records must be legible, maintained in the patient’s chart, and made available upon request.
Document disease stage, prior systemic therapies, and clinical indication for testing (e.g., progression, recurrence, treatment selection).

Documentation Required

Clinical context required

Order documentation must specify tumor type and clinical context to support testing—these tests are indicated primarily for advanced solid tumors and therapy selection.

State cancer type, disease stage (e.g., advanced/metastatic), line of therapy, and clinical question to be answered by testing (e.g., targeted therapy selection).
Indicate whether the test is being used for initial genotyping, detection of acquired resistance, or for therapy selection after progression.

Documentation Required

Test identification and specimen documentation

When ordering, document the specific FDA-cleared or validated assay and the specimen type provided. This assists reviewers in assessing conformity with test labeling and analytic/clinical validity.

Specify the exact assay name and manufacturer (e.g., FoundationOne Liquid CDx, Guardant360 CDx, Tempus xT CDx).
Document specimen type (plasma, FFPE tumor tissue, blood collection tube type), collection date/time, and adequacy (e.g., tumor fraction if available).
If reflex testing is anticipated (e.g., tissue reflex after low ctDNA TF), document the reflex plan in the order or record.

Documentation Required

Medical record support required

Medical records may be required to substantiate clinical criteria during claims or PA review. Ensure records fully support medical necessity and the rationale for testing.

Provide prior test results, imaging, pathology reports, and treatment history when available.
If concurrent testing is requested, include justification (e.g., tumor type where concurrent testing is medically necessary per policy).
Anticipate requests for documentation when tests are performed outside FDA-labeled indications or for non-CDx assays.

Note

Testing sequence considerations

Testing sequence can affect diagnostic yield and time to treatment. Simultaneous tissue and liquid testing or initial liquid testing with reflex to tissue can shorten time to treatment and reduce need for repeat procedures when tissue is insufficient.

Consider simultaneous testing for patients with suspected advanced NSCLC or advanced/metastatic breast cancer where concurrent testing is recognized as medically necessary by this policy.
An initial liquid biopsy with reflex to tissue testing is reasonable when rapid results are needed or when tissue biopsy is high risk, but note lower sensitivity when ctDNA TF is low.

Step Therapy

Step therapy context

Guideline context: routine testing for activating mutations (e.g., PIK3CA, AKT1, PTEN) is recommended to guide targeted therapies in certain cancers; document guideline-based indications when applicable.

Include guideline citations or rationale in the record when ordering tests to support therapy selection.
Step-therapy or sequencing of systemic agents may depend on identified activating mutations; ensure documentation ties testing to intended therapeutic decision-making.

Trial prespecified cut-pointsKEYNOTE-158 prespecified ≥10 and ≥13 mut/Mb using FoundationOne CDx; the regulatory cutpoint for CDx indication was 10 mut/Mb.

Intended use requirementTMB must be determined by an FDA-approved test to support the TMB-high indication for pembrolizumab.

Billing Rule

Order using validated NGS platforms or FDA-approved CDx assays

Order CDx testing using a clinically validated NGS platform or an FDA-approved companion diagnostic as recommended by specialty guidelines; liquid biopsies are acceptable when clinically appropriate.

Use FDA-cleared/approved CDx assays or validated NGS platforms per NCCN/ASCO/IASLC guideline recommendations.
Select liquid biopsy CDx (e.g., FoundationOne Liquid CDx, Guardant360 CDx) when tissue is not feasible or as complementary testing.

Billing Rule

Order in compliance with benefit rules and use CLIA-regulated labs

Place orders in accordance with federal, state, and contractual benefit plan rules and use CLIA-regulated laboratories for genetic testing; consult the FDA list to confirm CDx status when needed.

Laboratories performing genetic tests must be CLIA-regulated; verify lab certification as part of ordering.
Confirm companion diagnostic status via FDA's List of Cleared or Approved Companion Diagnostic Devices when necessary for coverage determination.

Assay gene content (FoundationOne Liquid CDx)

Detects and reports genomic alterations in 311 genes using cfDNA from plasma.

Analytic validation summaryValidation studies reported high reproducibility and sensitivity (e.g., overall positive percent agreement ~96.3%; detectable ctDNA in large series ~94%).

Frequency limits — general statement

Document scopeThis document portion does not specify numeric frequency limits for CDx testing; coverage is guided by clinical indication and test criteria.

Concurrent testing noteConcurrent tissue-based and liquid biopsy CDx testing is defined and permitted in select advanced/metastatic cancers (see policy for 30-day concurrent testing definition).

Subsequent-use triggerRepeat testing on a new specimen is covered when the patient has disease recurrence, progression, or lacked response to most recent systemic therapy.

FDA-cleared or approved CDx tests — Subsequent use on a new specimen

Permitted subsequent useSubsequent use of an FDA-cleared or approved CDx test on a new specimen is allowed when the test criteria are met and the individual has disease recurrence, cancer progression, or did not respond to the most recent systemic therapy.

Criteria prerequisiteThe test must meet the policy criteria (FDA CDx listing or FDA approval order for the intended therapeutic product and clinical indication).

Coverage intentRepeat testing is intended to inform therapy selection after clinical change rather than as routine-repeat without new clinical indication.

Specimen type examples

Liquid biopsy typically uses plasma cfDNA collected from peripheral whole blood in dedicated collection tubes (e.g., FoundationOne Liquid CDx, Guardant360 CDx).

Clinical considerationsctDNA detection sensitivity depends on circulating tumor DNA fraction; low ctDNA TF (<1%) reduces detection sensitivity and may necessitate reflex tissue biopsy.

Concurrent Testing — definition and policy context

DefinitionConcurrent Testing: tissue-based testing and Liquid Biopsy ordered for the same clinical indication within a 30-day period.

Policy allowanceConcurrent use of tissue-based and liquid biopsy FDA-cleared/approved CDx tests within 30 days is considered proven and medically necessary for advanced/metastatic (stage IV) breast cancer and stage IV NSCLC when criteria are met.

Revision noteDefinition of Concurrent Testing was added in the policy revision and used to permit specified concurrent testing scenarios.

Assay identification examples and specimen types

Assay examplesExamples of FDA-cleared/approved CDx assays include FoundationOne Liquid CDx (plasma cfDNA), Guardant360 CDx (plasma cfDNA), and MI Cancer Seek (FFPE tumor tissue).

Specimen typesFoundationOne Liquid CDx and Guardant360 CDx use plasma cfDNA from peripheral blood; MI Cancer Seek and other listed assays use FFPE tumor tissue nucleic acid.

Assay contentAssays vary widely in gene content (e.g., FoundationOne Liquid CDx: 311 genes; Guardant360 CDx: 55 genes; MI Cancer Seek: 228 genes; TruSight: 517 genes; xT CDx: 648 genes).

Tumor Mutational Burden (TMB) — definition and threshold

DefinitionTumor Mutational Burden (TMB): a measure of mutations per megabase (mut/Mb) reported by some CGP assays and used to define TMB-high populations in trials.

Example thresholdAn example TMB-high threshold used in regulatory and trial contexts is ≥ 10 mut/Mb (FoundationOne CDx cutpoint for pembrolizumab approval).

Clinical evidenceKEYNOTE-158 demonstrated higher response rates to pembrolizumab in participants with TMB ≥10 mut/Mb determined by FoundationOne CDx.

NGS-based in vitro diagnostic (CDx) — definition

DefinitionNGS-based in vitro diagnostic (CDx): a laboratory assay using next-generation sequencing to detect genomic alterations such as SNVs, insertions/deletions, copy number changes, and fusions, and report biomarkers like MSI and TMB from FFPE tissue or plasma.

Assay capabilitiesThese CDx assays can detect substitutions, indels, rearrangements/fusions, and copy number alterations and may report complex biomarkers (e.g., MSI, TMB).

Intended specimen typesNGS-based CDx assays use DNA/RNA from FFPE tumor tissue, matched normal specimens, or circulating cell-free DNA from plasma depending on the test's design.

ctDNA (liquid biopsy) — definition and clinical considerations

DefinitionctDNA (circulating tumor DNA): tumor-derived fragmented DNA detectable in plasma and assessed by liquid biopsy assays to identify tumor genomic alterations.

Detection considerationsctDNA detection and test sensitivity correlate with circulating tumor DNA tumor fraction (TF); higher TF increases sensitivity and may obviate reflex tissue testing; low TF (<1%) reduces sensitivity.

Clinical utilityctDNA may uniquely identify actionable variants not found in tissue and can be used complementarily with tissue testing; concurrent testing can increase actionable variant detection.

Concurrent Testing — revision and definition

Revised definitionConcurrent Testing (revision): concurrent use of tissue-based and liquid biopsy-based FDA-cleared/approved CDx tests within a defined interval (30 days) for the same clinical indication.

Policy applicationRevision added this definition to permit specified concurrent testing (stage IV breast cancer and stage IV NSCLC) when CDx criteria are met.

Documentation expectationConcurrent testing must meet the CDx criteria and be documented in the medical record to support medical necessity for coverage review.

coverage_clarification

Clarified that FDA cleared or approved CDx tests not explicitly listed are covered when the test will inform use of a targeted therapeutic and appears in the FDA Cleared or Approved Companion Diagnostic Devices Table or has an approval order in the FDA PMA database.

subsequent_testing_rule

Defined coverage for subsequent use of an FDA-cleared/approved CDx test on a new specimen when disease recurrence, progression, or lack of response to most recent systemic therapy occurs.

concurrent_testing_definition

Concurrent testing (tissue-based CDx plus liquid biopsy-based CDx) was defined and coverage permitted for advanced/metastatic (stage IV) breast cancer and stage IV NSCLC when criteria are met.

documentation_and_codes_update

Added medical records documentation requirements for coverage review; added CPT codes 0211U and 0523U and removed older CPT codes (0179U, 81445, 81449, 81450, 81451, 81455, 81456, 81599).