CurrentCapital BluecrossPolicy MP 2.388

MEDICAL POLICY SOMATIC BIOMARKER TESTING FOR IMMUNE CHECKPOINT INHIBITOR THERAPY (BRAF, MSIIMMR, PD-L1, TMB)

Defines medical necessity criteria for somatic biomarker testing (BRAF V600 variant, mismatch repair/microsatellite instability [MMR/MSI], PD-L1) to select individuals for immune checkpoint inhibitor therapy and states TMB testing is investigational. Applies to Capital Blue Cross products with program-specific variations.

Policy Summary

PayerCapital Bluecross

PolicyMEDICAL POLICY SOMATIC BIOMARKER TESTING FOR IMMUNE CHECKPOINT INHIBITOR THERAPY (BRAF, MSIIMMR, PD-L1, TMB)

Policy CodePolicy MP 2.388

Change TypeMaterial and administrative

Effective DateSep 1, 2025

Next Review Date

Key ActionEnsure the individual does not have any FDA-labeled contraindications to the requested immune checkpoint inhibitor and that the agent is intended to be used consistent with the FDA-approved label; document medical necessity for testing and verify member benefit coverage and preauthorization requirements.

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.

Administrative updates added 0473U and CPT 81210 and removed Benefit Variations Section; disclaimer updated.

4Biomarkers with explicit medical necessity criteria (BRAF V600, MMR/MSI, PD-L1, TMB)

2Biomarkers considered investigational (TMB generally)

Coverage Summary

Defines medical necessity criteria for somatic biomarker testing (BRAF V600 variant, mismatch repair/microsatellite instability [MMR/MSI], and PD-L1) to select individuals for immune checkpoint inhibitor therapy and states TMB testing is investigational. Applies to Capital Blue Cross products with program-specific variations and may have benefit variations by product; providers should verify member benefit coverage and preauthorization requirements for the specific product. Policy number: MP 2.388. Effective date: 2025-09-01. Last review: 2025-06-25.

High-level key values

scope_summaryDefines medical necessity criteria for somatic biomarker testing (BRAF V600, MMR/MSI, PD-L1) to select individuals for immune checkpoint inhibitor therapy and states TMB testing is investigational. Applies to Capital Blue Cross products with program-specific variations.

statusCURRENT

policy_numberMP 2.388

effective_date2025-09-01

last_review2025-06-25

Biomarkers with explicit medical necessity criteria (BRAF V600, MMR/MSI, PD-L1, TMB)4

Biomarkers considered investigational (BRAF for non-specified indications, TMB generally)2

Medical Necessity Criteria

BRAF V600 Variant Testing - Medically Necessary

BRAF V600 variant testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy is considered medically necessary 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

BRAF V600 Variant Testing - Investigational/Not Covered

BRAF V600 variant testing is considered investigational in all other situations.

ANY of the following

Any indication not meeting the medically necessary criteria above

Mismatch Repair / Microsatellite Instability (MMR/MSI) Testing - Medically Necessary

MMR/MSI testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy may be considered medically necessary when ANY ONE of the following is met:

ANY of the following

Individuals with advanced endometrial carcinoma who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation
Individuals with unresectable or metastatic solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options
The individual does not have any FDA-labeled contraindications to the requested agent
Included as an AND condition in policy text; treated as required with the above indications

MMR/MSI Testing - Investigational/Not Covered

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

ANY of the following

Any indication not meeting the medically necessary criteria above

PD-L1 Testing - Medically Necessary

PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy may be considered medically necessary when ALL of the following apply:

ALL of the following

ONE OF
- Individuals with metastatic non-small cell lung cancer (NSCLC)
- Individuals with locally advanced or metastatic esophageal or gastroesophageal junction carcinoma that is not amenable to surgical resection or definitive chemoradiation after 1 or more lines of systemic therapy for patients with tumors of squamous cell histology
- Individuals with metastatic or unresectable, recurrent head and neck squamous cell carcinomas
- Individuals with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

PD-L1 Testing - Investigational/Not Covered

PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations.

ANY of the following

Any indication not meeting the medically necessary criteria above

Tumor Mutational Burden (TMB) Testing - Investigational

TMB testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy is considered investigational.

ANY of the following

All indications for TMB testing to select individuals for immune checkpoint inhibitor therapy

Provider Actions

Documentation Required

Document FDA-labeled contraindications and intended agent use

Ensure the individual's records document that they do not have any FDA‑labeled contraindications to the requested immune checkpoint inhibitor and that the intended agent will be used consistent with the FDA‑approved label. Maintain documentation to support the medical necessity of testing (e.g., indication, intended therapy, FDA‑label consistency) in the medical record.

Document absence of FDA‑labeled contraindications.
Document intended agent and that use is consistent with FDA‑approved label.
Retain evidence in the medical record supporting medical necessity for testing.

Prior Authorization

Prior authorization may be required per product

This policy applies to certain Capital Blue Cross programs and products and may be subject to benefit variations; providers should verify member benefit coverage and whether preauthorization or prior authorization is required for the specific product before ordering testing.

Verify member benefit coverage for the product.
Confirm preauthorization/prior authorization requirements prior to testing.

Coding

Referenced Procedure / Test Codes (coding information provided; identification does not denote coverage)mixed

81210
81301
88341
88342
88360
88361
81479
0037U
0473U

FoundationOne CDx is noted as the only U.S. Food and Drug Administration (FDA)–approved panel for estimating tumor mutational burden (TMB). MMR/MSI and PD-L1 testing have received FDA approvals for selecting immune checkpoint inhibitor therapy for specific cancer types and indications (MMR/MSI for certain colorectal, endometrial, and other unresectable/metastatic solid tumors; PD-L1 for several indications including metastatic non–small cell lung cancer and other tumor types).

Background & Evidence

Variants in the BRAF gene (notably BRAF V600 variants) activate the RAF–MEK–ERK signaling pathway and are common in melanoma; many advanced melanomas harbor BRAF variants and BRAF-targeted therapies (alone or with immunotherapy) can be effective, and the immune checkpoint inhibitor atezolizumab in combination with cobimetinib and vemurafenib is FDA approved for unresectable or metastatic BRAF V600 mutation–positive melanoma. Mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) reflect defects in DNA repair, are associated with high tumor mutational load, and predict potential responsiveness to anti–PD-L1 therapy; MSI testing is commonly performed using PCR for five biomarkers (MLH1, MSH2, MSH6, PMS1, PMS2). Programmed cell death ligand-1 (PD-L1) is a transmembrane protein expressed on tumor cells and other tissues; blocking PD-L1 can restore T-cell activity and FDA-approved PD-L1 inhibitors include atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. Tumor mutational burden (TMB) measures the number of gene mutations in cancer cells; while targeted NGS panels are used to estimate TMB, FoundationOne CDx is currently the only FDA-approved panel for estimating TMB.

Study/Source	Key Finding
IMspire150 trial	Atezolizumab with vemurafenib and cobimetinib improved median PFS (15.1 vs 10.6 months; HR 0.78; p=0.025) in unresectable advanced BRAF V600E-positive melanoma.
KEYNOTE-158 subgroup	Responses observed in tTMB-high patients; evidence insufficient to conclude net health benefit for TMB testing broadly.

Thresholds

Microsatellite instability - definitionHigh MSI defined as 2 or more of the 5 biomarkers showing instability or >30% of tested biomarkers showing instability depending on panel.

Definitions

High MSI: Defined as 2 or more of 5 biomarkers showing instability or >30% of tested biomarkers showing instability depending on panel.

Revision History

03/03/2025material

Major review: 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; policy guidelines, background, rationale, and references updated; coding reviewed and CPT 88360 and 88361 added.

06/25/2025administrativeLatest

Administrative updates: added code 0473U and CPT 81210; removed Benefit Variations Section and updated disclaimer.

Policy Summary

PayerCapital Bluecross

PolicyMEDICAL POLICY SOMATIC BIOMARKER TESTING FOR IMMUNE CHECKPOINT INHIBITOR THERAPY (BRAF, MSIIMMR, PD-L1, TMB)

Policy CodePolicy MP 2.388

Change TypeMaterial and administrative

Effective DateSep 1, 2025

Next Review Date

On This Page

Individuals with locally recurrent unresectable or metastatic hormone receptor-negative/HER2-negative (triple negative) breast cancer

Individuals with persistent, recurrent, or metastatic cervical cancer

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