CurrentCapital BluecrossPolicy MP 2.388

Somatic biomarker testing for immune checkpoint inhibitor therapy (BRAF, MSI/MMR, PD-L1, TMB)

Defines medical necessity criteria for somatic tumor testing (BRAF V600, MMR/MSI, PD-L1, and TMB) to select individuals for immune checkpoint inhibitor therapy for Capital BlueCross-administered products, with program/product variations noted.

Policy Summary

PayerCapital Bluecross

PolicySomatic biomarker testing for immune checkpoint inhibitor therapy (BRAF, MSI/MMR, PD-L1, TMB)

Policy CodePolicy MP 2.388

Change TypeRevised (added MMR/MSI and PD-L1 indications); coding updates

Effective DateSep 1, 2025

Next Review Date

Key ActionProviders must ensure the individual does not have FDA-labeled contraindications and that the agent will be used consistent with the FDA-approved label when ordering testing.

POLICY UPDATE CHANGES

Added policy statement to include MMR/MSI testing for individuals with advanced or metastatic colorectal cancer and PD-L1 testing for individuals with metastatic non-small cell lung cancer.

Background and Rationale updated; coding reviewed and 88360 and 88361 added.

Added indications related to immunotherapy from MP 2.364 and added CPT 81210 from MP 2.364.

Added CPT/Proprietary code 0473U to coding list.

Removed Benefit Variations Section and updated Disclaimer.

4Biomarkers addressed (BRAF V600, MMR/MSI, PD-L1, TMB)

multipleCovered Indications (selected cancers listed)

MP 2.388

Coverage Summary

Scope: This policy defines medical necessity criteria for somatic tumor testing (BRAF V600, MMR/MSI, PD-L1, and TMB) to select individuals for immune checkpoint inhibitor therapy for Capital BlueCross-administered products, with program/product variations noted. Policy number MP 2.388 and subject: Somatic biomarker testing for immune checkpoint inhibitor therapy (BRAF, MSI/MMR, PD-L1, TMB).

Effective date: 9/1/2025; Last review: 2025-03-03.

Coverage stance: mixed — some biomarker tests and indications are covered when medical necessity criteria are met, while others are considered investigational.

Biomarkers addressed: BRAF V600, MMR/MSI, PD-L1, and Tumor Mutational Burden (TMB).

Quick Facts

Policy NumberMP 2.388

Effective Date9/1/2025

Last Review2025-03-03

Next Review

Biomarkers addressedBRAF V600, MMR/MSI, PD-L1, TMB (4)

Coverage stanceMixed (covered for specified indications; investigational for other uses)

MSI-H thresholdHigh MSI = 2 or more of 5 biomarkers unstable OR >30% of tested biomarkers unstable (depending on panel)

Medical-Necessity Criteria

BRAF V600 Variant Testing - Medically Necessary

Covered when ALL of the following are met:

ALL of the following

Individual has unresectable or metastatic melanoma
The individual does not have any FDA-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label

MMR/MSI Testing - Medically Necessary

Covered when ANY of the following are met:

ANY of the following

Individuals with advanced or metastatic colorectal cancer

Not Covered / Experimental Criteria

BRAF V600 Variant Testing - Investigational

Not covered / investigational

Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations (i.e., situations NOT meeting the medically necessary criteria) is considered investigational

There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

MMR/MSI Testing - Investigational

Not covered / investigational

MMR/MSI testing to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations

There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure for these indications.

PD-L1 Testing - Investigational

Coding

Covered when medically necessary (codes listed in policy)mixedCovered

81210	BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene; V600
81301	KRAS gene mutation analysis (example description; code listed)
88341	Immunohistochemistry, per specimen; initial single antibody stain
88342	Immunohistochemistry, per specimen; each additional single antibody stain
88360	Morphometric analysis, per specimen (listed in coding review)
88361	Morphometric analysis, each additional specimen (listed in coding review)
81479	Unlisted molecular pathology procedure
0037U	Proprietary or genomic test code (listed)
0473U	Proprietary or genomic test code (listed)
C00-D49	ICD-10 Cancer Diagnosis Range (listed as description)

Notemixed

No codes listed

Provider Actions

Documentation Required

Align testing with FDA-labeled agent use

Providers must ensure the individual does not have FDA-labeled contraindications to the requested agent and that the agent will be used consistent with the FDA-approved label when ordering testing to select for therapy.

Prior Authorization

Medical necessity required

Testing is covered only when medical necessity criteria in this policy are met and coverage is subject to member benefit terms; providers should obtain any required prior authorization per member benefits.

Testing is covered only when medical necessity criteria in this policy are met.
Coverage is subject to member benefit terms; obtain any required prior authorization per member benefits.

Background and Evidence

Background: The policy summarizes evidence and rationale for biomarker testing to select immune checkpoint inhibitor therapy. For BRAF V600, variants are common in advanced melanoma and BRAF-targeted therapy combined with immunotherapy (e.g., atezolizumab + cobimetinib + vemurafenib) has FDA approval and NCCN recommendations supported by randomized trial data (IMspire150) showing improved progression-free survival.

For MMR/MSI, deficiency and MSI-H identify tumors with high mutational load that may respond to anti–PD-L1 therapy. FDA approvals and NCCN recommendations support MMR/MSI testing to select immune checkpoint inhibitor therapy in advanced/metastatic colorectal cancer, certain endometrial cancers, and some unresectable/metastatic solid tumors that have progressed after prior therapy.

For PD-L1, PD-L1 testing has FDA approvals and NCCN recommendations to select immune checkpoint inhibitor therapy for multiple indications including metastatic non–small cell lung cancer, recurrent/metastatic head and neck squamous cell carcinoma, certain esophageal/gastroesophageal junction cancers, HER2-positive gastric/gastroesophageal junction adenocarcinoma, persistent/recurrent/metastatic cervical cancer, and locally recurrent unresectable or metastatic triple-negative breast cancer.

TMB testing: evidence is currently insufficient — TMB testing to select individuals for immune checkpoint inhibitor therapy is considered investigational.

Additional considerations: Repeat genomic testing may be useful at time of cancer progression because tumor molecular profiles can change; ASCO suggests repeat genomic testing for suspected acquired resistance when next-line therapy choice would be guided by results.

Policy context: Testing for FDA-approved companion diagnostics and tests with NCCN 2A+ recommendations are implemented per guidance; coding and administrative updates (including added CPT/Proprietary codes and coding review) have been made in recent updates.

Revision History

04/11/2024clarified

Added indications related to immunotherapy from MP 2.364 and added CPT 81210 from MP 2.364; no change to policy statements at that time.

07/01/2024added

Added CPT/Proprietary code 0473U to coding list.

03/03/2025revised (material)

Background and Rationale updated; coding reviewed and 88360 and 88361 added; added policy statement to include MMR/MSI testing for individuals with advanced or metastatic colorectal cancer and PD-L1 testing for individuals with metastatic non-small cell lung cancer.