UnitedHealthcare Companion Diagnostic Coverage Update

Coverage Criteria for Companion Diagnostic and Genomic Testing

Coverage criteria for tumor genomic profiling

Covered when ALL of the following are met (per evidence and guideline recommendations):

ALL of the following

The individual has an advanced or metastatic (stage III/IV) solid tumor or hematologic malignancy for which genomic profiling could change management (e.g., identify an FDA-approved, guideline-recommended, or tumor-agnostic therapy).
Consistent with ASCO and ESMO recommendations to perform tumor NGS in advanced/metastatic cancers when actionable biomarker-linked therapies exist.
Testing is ordered by a qualified provider and will be performed in a CLIA-certified laboratory or equivalent.
Testing used to inform clinical care must be done in an appropriately certified laboratory (ASCO).
The test is intended to detect genomic alterations that have established clinical actionability (e.g., biomarkers with FDA-approved therapies, NCCN/ASCO/ESMO guideline–supported indications, or ESCAT level I alterations).
Multigene panels are recommended when the individual is eligible for genomic biomarker-linked, approved therapy or when more than one actionable biomarker is possible (ASCO; ESMO).
For tumor mutational burden (TMB) or other biomarkers that are drug-label linked, the assay and cut-point align with the specific FDA companion diagnostic or the FDA-cleared/approved test used in the supporting clinical trial (for example, pembrolizumab TMB-high indication aligned to FoundationOne CDx and the ≥10 mut/Mb cut-point).
FDA alignment required when coverage is sought based on companion diagnostic labeling; FDA approval alone is informational and not sufficient for coverage without alignment to applicable FDA CDx labeling.
When tissue is unavailable or unobtainable, cfDNA/liquid biopsy testing may be used as an initial alternative for detection of actionable alterations, provided the limitations of the assay (sensitivity for fusions, copy-number changes, low tumor fraction) are recognized and a negative liquid biopsy is reflexed to tissue testing when feasible.
Reflects ASCO and ESMO guidance that cfDNA is useful when tissue is not available and negative liquid results should be confirmed in tissue if actionable alterations are suspected.
Use of broad comprehensive genomic profiling (CGP) on tissue or ctDNA is covered when results are expected to directly inform treatment selection with therapies that have demonstrated clinical benefit or where guideline recommendations support such testing; CGP for purely exploratory purposes without linkage to actionable management is not supported.
Based on guideline recommendations and Hayes assessments indicating limited utility of broad CGP outside contexts tied to actionable therapies or trials.
Germline testing should be performed when results could influence therapy selection (e.g., PARP inhibitor eligibility) or when pathogenic/likely pathogenic variants are identified on tumor testing; individuals with P/LP germline findings should be referred for genetic counseling.
Per ASCO recommendations for germline testing in advanced/metastatic settings.
Tests intended solely for population screening, early-stage routine surveillance, or routine monitoring without demonstrated clinical utility (including many ctDNA assays for MRD or screening) are not covered under this tumor genomic profiling criterion.
Reflects insufficient evidence for ctDNA assays in early-stage cancer screening, routine monitoring, or MRD-directed interventions (ASCO, Hayes).

Covered Indications and Use Cases

Oncology indications with FDA CDx–drug alignment

Oncology indications where a CDx and biomarker pair is on the FDA List of Cleared or Approved Companion Diagnostic Devices and use aligns with drug labeling:

FDA-listed companion diagnostic indications: Use of CDx testing to identify individuals most likely to benefit, at increased risk for side effects, or requiring monitoring for response when the cancer/drug/biomarker/specimen pairing appears on the FDA List of Cleared or Approved Companion Diagnostic Devices and use aligns with drug labeling

Alignment with FDA CDx list required

TMB testing for pembrolizumab (FDA-approved assay, ≥10 mut/Mb)

TMB testing by an FDA-approved assay for pembrolizumab eligibility:

TMB assay and cutoff: TMB must be determined by an FDA-approved assay (e.g., FoundationOne CDx) using a prespecified TMB-high cut-point of ≥10 mutations per megabaseTMB ≥10 mut/Mb

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Prior Authorization / FDA Alignment Considerations

Prior authorization is not explicitly specified in the extracted sections of this policy for most Companion Diagnostic (CDx) and comprehensive genomic profiling (CGP) tests. However, when a CDx is intended to support use of an FDA-approved therapeutic product, providers should document that the requested test aligns with the FDA-listed companion diagnostic device for the specific drug, indication, and specimen type. Requests that do not match an FDA-listed drug/biomarker/specimen pairing or that lack documentation of the FDA-cleared/approved assay and result carry a risk of denial and may require prior authorization review to confirm alignment with the FDA CDx listing or medical-policy coverage rules.

Document the specific companion drug and FDA indication when ordering to demonstrate alignment with the FDA List of Cleared or Approved Companion Diagnostic Devices.
Provide assay name, specimen source, and numeric/qualitative result when the drug label requires an FDA-approved/cleared test (e.g., TMB for pembrolizumab per F1CDx).
Repeat CDx testing on a new tissue or liquid biopsy is considered medically necessary up to three times annually when criteria are met; include clinical justification (recurrence, progression, or lack of response to recent systemic therapy).
Concurrent tissue and liquid biopsy testing ordered within 30 days for advanced/metastatic (stage IV) breast cancer or advanced/metastatic (stage IV) NSCLC is considered medically necessary when CDx criteria are met.
When no FDA CDx match exists for the cancer/drug pairing, refer to the Molecular Oncology Testing policies for coverage determination.

Coding and Test Identifiers

Applicable CPT/PLA codes (examples, contiguous listing continued)mixed

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

Applicable CPT/PLA codes (continued)mixed

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.
0179U	Oncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without prior knowledge of partner/breakpoint, copy number variations), with report of significant mutation(s).
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.
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.

Applicable CPT codes and unlisted codesmixed

81445	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; DNA analysis or combined DNA and RNA analysis.
81449	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; RNA analysis.
81450	Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis.
81451	Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis.
81455	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis.
81456	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis.
81479	Unlisted molecular pathology procedure.
81599	Unlisted multianalyte assay with algorithmic analysis.

Test codes (not specified in excerpt)mixed

not listed

Specific CPT/HCPCS codes are not provided in this document excerpt.

Tumor Mutational Burden (TMB) — FDA/F1CDx and study thresholds

FDA/F1CDx-defined TMB-highTMB-high defined as ≥10 mutations per megabase (mut/Mb) for the pembrolizumab CDx indication (F1CDx).

Study-defined TMB threshold (exome)Some analyses define high TMB as ≥175 mutations per exome (reported in retrospective evaluations).

Clinical context for pembrolizumab useTMB must be determined by an FDA-approved test and individuals must have progressed following prior treatment with no satisfactory alternative; KEYNOTE-158 supported approval (ORR ~29%).

TMB cut-point — ≥ 10 mut/Mb

TMB cut-point (policy)TMB ≥ 10 mut/Mb is the prespecified cut-point used by F1CDx and in KEYNOTE-158 to define TMB‑high for pembrolizumab eligibility.

Not Covered Uses

NOT COVERED: Requests for Companion Diagnostic testing that do not have a corresponding cancer/diagnostic pairing on the FDA List of Cleared or Approved Companion Diagnostic Devices are not covered under this policy and should be referred to the Molecular Oncology Testing policies for solid tumor or hematologic cancers for determination of coverage.

NOT COVERED: Use of specific commercial broad profiling tests (examples cited in external assessments) for broad molecular profiling to direct therapy is not covered when there is inadequate evidence of clinical validity or utility. The policy cites independent evaluations that found insufficient peer-reviewed evidence to support routine use of these tests for broad panel-directed treatment selection outside of FDA-labeled indications or clinical trials.

NOT COVERED: Liquid biopsy tests intended for general population screening or for early detection of colorectal cancer/high-risk adenomas are not covered due to insufficient evidence of clinical utility in these screening applications.

NOT COVERED: Use of ctDNA assays for cancer screening, routine use in early-stage disease for treatment decision-making, or for molecular residual disease detection without demonstrated clinical utility is not covered under this policy.

NOT COVERED: Tests or intended uses that do not match an FDA-listed companion diagnostic and its labeled drug indication and specimen are not covered. FDA marketing clearance or approval is informational only; coverage requires alignment with the FDA CDx listing and the companion drug label.

Background and Evidence Summary

Background: A Companion Diagnostic (CDx) test identifies a biomarker required to select or safely use a specific therapeutic drug and is intended to direct treatment decisions per the drug labeling. Coverage is tied to CDx–drug pairings listed on the FDA List of Cleared or Approved Companion Diagnostic Devices, and CDx uses are judged based on alignment with FDA labeling, analytic validation, and demonstration of clinical utility in the indicated cancer context.

Definitions

Companion Diagnostic Test definition

DefinitionCompanion Diagnostic Test: a test that provides important information for the safe and effective use of a corresponding therapeutic drug (FDA).

PurposeUsed to identify biomarkers necessary to select or monitor patients for a specific drug according to the drug label.

Regulatory linkageCoverage requires alignment with the drug indication, biomarker, and specimen on the FDA List of Cleared or Approved Companion Diagnostic Devices.

Liquid Biopsy definition

DefinitionLiquid Biopsy: minimally invasive testing of bodily fluids (most commonly blood) to identify tumor-derived cells or circulating tumor DNA/RNA and other analytes for detection, treatment selection, or monitoring.

SpecimensCommon specimens include blood, urine, cerebrospinal fluid, pleural fluid, and other bodily aspirates.

Provider Resources and Practical Considerations

Documentation Required

Specimen collection and analytic validation documentation

Specimen collection procedures and analytical validation details (for example, tube type, limits of detection, and reproducibility) should be documented and available in the laboratory report.

Example analytic details reported include 95% LoD 0.40% VAF for select substitutions/indels and tumor fraction thresholds for copy number detection.

Denial Risk

Low tumor fraction limits liquid biopsy sensitivity

Low ctDNA tumor fraction reduces sensitivity of liquid biopsy tests; negative or non‑actionable results at low tumor fraction may necessitate reflex tissue testing or cautious interpretation.

Median tumor fraction reported was 2.2% in a large series; sensitivity for tissue‑identified alterations approaches 100% at tumor fraction ≥10% but is lower at smaller tumor fractions.

Revision History

2025-04-01policy_revisionLatest

Revised coverage guidelines to require that Companion Diagnostic Tests align with the drug, FDA-approved indication, and appropriate tissue/specimen on the FDA List of Cleared or Approved Companion Diagnostic Devices

2025-04-01policy_addition

Added allowance for repeat Companion Diagnostic Testing on a new tissue or liquid biopsy specimen up to three times annually when clinical criteria (recurrence, progression, or lack of response) are met

2025-04-01

OpenPayer

FDA Cleared or Approved Companion Diagnostic Testing