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A.2.04.157
Multiple biomarkers are being evaluated to predict response to immunotherapy for individuals with cancer. Immune checkpoint inhibitors and associated companion diagnostic tests for these therapies have received U.S. Food and Drug Administration approval for cancer-specific and, more recently, tumor agnostic indications. Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher. Pivotal evidence is included in the table below for informational purposes.
Immune Checkpoint Inhibitors and Associated Biomarkers
Immune checkpoint inhibitors are a type of cancer immunotherapy used to treat a wide range of cancer types, often in individuals with advanced or metastatic disease for which other treatment options are unavailable.
Currently, there are 11 FDA-approved immune checkpoint inhibitors:
Atezolizumab (Tecentriq®)
Avelumab (Bavencio®)
Cemiplimab (Libtayo®)
Dostarlimab-gxly (Jemperli®)
Durvalumab (Imfinzi®)
Ipilimumab (Yervoy®)
Nivolumab (Opdivo®)
Pembrolizumab (Keytruda®)
Tremelimumab (Imjudo®)
Retifanlimab (Zynyz®)
Toripalimab (loqtorzi®)
Multiple biomarkers have been identified as predictive of response to immune checkpoint inhibitor therapy. Some biomarker tests are required as part of FDA labeled indications and are routinely used to select individuals for treatment. The following section provides a brief overview of these biomarkers. Refer to the table below for a complete list of currently available immune checkpoint inhibitors, their labeled indications, and associated companion diagnostic biomarker tests.
BRAF V600
Variants in the b-raf proto-oncogene, serine/threonine kinase (BRAF) kinase gene are common in tumors of individuals with advanced melanoma and result in constitutive activation of a key signaling pathway (RAF-mitogen-activated protein kinase (MEK)-ERK pathway) that is associated with oncogenic proliferation. In general, 50% to 70% of melanoma tumors harbor a BRAF variant; of these, 80% are positive for the BRAF V600E variant, and 16% are positive for BRAF V600K. Thus, 45% to 60% of patients with advanced melanoma may respond to a BRAF inhibitor targeted to this mutated kinase. BRAF inhibitors may be used alone or in combination with immunotherapy in individuals with BRAF pathogenic variants. The immune checkpoint inhibitor atezolizumab (Tecentriq) is FDA approved in combination with cobimetinib and vemurafenib in individuals with BRAF V600 mutation-positive unresectable or metastatic melanoma.
BRAF testing is also used for indications outside the scope of this policy (e.g., to select individuals for targeted treatment with BRAF or MEK inhibitors); refer to the following related policies:
: BRAF testing for BRAF inhibitors in NSCLC
Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)
Mismatch Repair Deficiency/Microsatellite Instability
Mismatch repair deficiency (dMMR) and high levels of microsatellite instability (MSI-H) describe cells that have alterations in certain genes involved in correcting errors made when DNA is replicated. dMMR tumors are characterized by a high tumor mutational load and potential responsiveness to anti-programmed cell death ligand-1 (PD-L1)-immunotherapy. Mismatch repair (MMR) deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, but it may also be found in other cancers including breast cancer.
Testing for dMMR and MSI is used to identify individuals most likely to respond to anti-PD-L1 therapy. Either MMR testing or MSI testing can be used to screen for MMR functional defects. MMR testing is performed using IHC for 4 MMR proteins (MLH1, MSH2, PMS2, and MSH6). Microsatellite instability testing is generally performed using polymerase chain reaction (PCR) for 5 biomarkers (MLH1, MSH2, MSH6, PMS1 and PMS2). High MSI is defined as 2 or more of the 5 biomarkers showing instability or more than 30% of the tested biomarkers showing instability depending on what panel is used.
Programmed Cell Death Ligand Protein-1
Programmed cell death ligand-1 is a transmembrane protein expressed on the surface of multiple tissue types, including many tumor cells. Blocking the PD-L1 protein may prevent cancer cells from inactivating T cells.
FDA-approved PD-L1 immune checkpoint inhibitors include atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.
Tumor Mutational Burden
Tumor mutational burden (TMB) is a measure of gene mutations within cancer cells. Initially, assessments of TMB involved whole exome sequencing (WES). More recently, targeted next generation sequencing (NGS) panels are being adapted to estimate TMB. Currently FoundationOne CDx is the only U.S. Food and Drug Administration (FDA) approved panel for estimating TMB, but others are in development.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. FDA has chosen not to require any regulatory review of these tests.
The table below summarizes currently available immune checkpoint inhibitors with FDA approval, and the FDA cleared or approved companion diagnostic tests associated with each. An up-to-date list of FDA cleared or approved companion diagnostics is available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools .
FDA Companion Diagnostic Tests for Immune Checkpoint Inhibitor Therapy
Biomarker | Immune Checkpoint Inhibitor | Indication | FDA-Approved Companion Diagnostic Tests | Pivotal Studies | NCCN Recommendation Level/Guideline |
BRAF V600 | Atezolizumab (Tecentriq) + cobimetinib (Cotellic) + vemurafenib (Zelboraf) | Patients with BRAF V600 mutation-positive unresectable or metastatic melanoma | FoundationOne® CDx | IMspire150NCT02908672 | 2A or higher/Cutaneous Melanomaª |
dMMR/MSI-H | Nivolumab (Opdivo) +/- Ipilimumab (Yervoy) | Patients ≥12 years of age with dMMR or MSI-H metastatic colorectal cancer that has progressed following treatment, as a single agent or in combination with ipilimumab* | None | CHECKMATE-142 NCT02060188 | 2A or higher/Colon Cancerb |
dMMR/MSI-H | Pembrolizumab (Keytruda) | Adult and pediatric patients with unresectable or metastatic dMMR or MSI-H solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options* Safety and effectiveness in pediatric patients with MSI-H central nervous system cancers have not been established Melanoma for the treatment of patients with unresectable or metastatic melanoma. for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Malignant Pleural Mesothelioma (MPM) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with unresectable advanced or metastatic MPM. Head and Neck Squamous Cell Cancer (HNSCC) in combination with platinum and fluorouracil (FU) for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma (cHL) for the treatment of adult patients with relapsed or refractory cHL. for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Gastric Cancer in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test*. in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Esophageal Cancer for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after 1 or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Cervical Cancer in combination with chemoradiotherapy, for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Hepatocellular Carcinoma (HCC) for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer. Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) or not MSI-H as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. as a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer (TNBC) for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. | Ventana® MMR RxDx (dMMR) FoundationOne CDx (MSI-H)MI Cancer Seek™ (MSI-H) | KEYNOTE-158NCT02628067 | None |
dMMR/MSI-H | Pembrolizumab (Keytruda) | Patients with unresectable or metastatic MSI-H or dMMR CRC as determined by an FDA-approved test | None | KEYNOTE-177 NCT02563002 | 2A or higher/Colon Cancerb |
pMMR/MSI-H | Pembrolizumab (Keytruda) + Lenvatinib (Lenmiva) | Patients with advanced endometrial carcinoma that is pMMR as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation | Ventana MMR RxDxMI Cancer Seek (Not MSI-H) | KEYNOTE-775NCT03517449 | 2A or higher/Uterine Neoplasmsc |
dMMR/MSI-H | Dostarlimab (Jemperli) | Adult patients with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options* Endometrial Cancer: in combination with carboplatin and paclitaxel, followed by JEMPERLI advanced or recurrent endometrial cancer. as a single agent for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced EC, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen in any setting and are not candidates for curative surgery or radiation. | Ventana MMR RxDx PanelMI Cancer Seek (MSI-H) | GARNET NCT02715284 | |
dMMR | Dostarlimab (Jemperli) | Adult patients with dMMR recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen* | Ventana MMR RxDx Panel | RUBY NCT03981796 | 2A or higher/Uterine Neoplasmsc |
PD-L1 | Pembrolizumab (Keytruda) | First-line treatment of patients with NSCLC expressing PD-L1 as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic Patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy | PD-L1 IHC 22C3 pharmDx | KEYNOTE-024 NCT02142738 | 2A or higher/Non-Small Cell Lung Cancerd |
PD-L1 | Pembrolizumab (Keytruda) | First-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 as determined by an FDA-approved test | PD-L1 IHC 22C3 pharmDx | KEYNOTE-048NCT05252429 | 2A or higher/Head and Neck Cancerse |
PD-L1 | Pembrolizumab (Keytruda) | Patients with locally advanced or metastatic esophageal or gastroesophageal junction carcinoma that is not amenable to surgical resection or definitive chemoradiation as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 as determined by an FDA-approved test | PD-L1 IHC 22C3 pharmDx | KEYNOTE-590NCT03881111 | 2A or higher/Esophageal and Esophagogastric Junction Cancersf |
PD-L1 | Pembrolizumab (Keytruda) | In combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.* | PD-L1 IHC 22C3 pharmDx | KEYNOTE-811 NCT03615326 | 2A or higher/Gastric Cancerg |
PD-L1 | Pembrolizumab (Keytruda) | In combination with chemotherapy, with or without bevacizumab, patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test As a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS≥1) as determined by an FDA-approved test | PD-L1 IHC 22C3 pharmDx | KEYNOTE-826NCT03635567 | 2A or higher/Cervical Cancerh |
PD-L1 | Pembrolizumab (Keytruda) | In combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA approved test | PD-L1 IHC 22C3 pharmDx | KEYNOTE-355NCT02819518 | 2A or higher/Breast Canceri |
PD-L1 | Cemiplimab (Libtayo®) | First-line treatment of adult patients with NSCLC whose tumors have high PD-L1 expression (TPS≥ 50%) as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations, and is: locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic | PD-L1 IHC 22C3 pharmDxVentana PD-L1 (SP263) Assay | EMPOWER-Lung 1 NCT03088540 | 2A or higher/Non-Small Cell Lung Cancerd |
PD-L1 | Nivolumab (Opdivo) + Ipilimumab (Yervoy) | Patients with metastatic NSCLC expressing PD-L1 as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations | PD-L1 IHC 28-8 pharmDx | CHECKMATE-227 NCT02477826 | 2A or higher/Non-Small Cell Lung Cancerd |
PD-L1 | Atezolizumab (Tecentriq) | Adult patients with Stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥1% of tumor cells, as determined by an FDA-approved test | Ventana PD-L1 (SP263) AssayVentana PD-L1 (SP142) Assay | NCT02409342 | 2A or higher/Non-Small Cell Lung Cancerd |
PD-L1 | Atezolizumab (Tecentriq) | Patients with locally advanced or metastatic urothelial carcinoma whose tumors have PD-L1 expression ≥5% of tumor cells, as determined by an FDA-approved test, and is: have disease progression during or following platinum-containing chemotherapy have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy | Ventana PD-L1 (SP142) Assay | IMvigor210 NCT02951767 & NCT02108652 | 2B/Bladder Cancerj |
TMB | Pembrolizumab (Keytruda) | Adult and pediatric patients with unresectable or metastatic TMB-high (≥10 mutations/megabase) solid tumors, as determined by an FDA-approved test that have progressed following prior treatment and who have no satisfactory alternative treatment options Melanoma for the treatment of patients with unresectable or metastatic melanoma. for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. Non-Small Cell Lung Cancer (NSCLC) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first-line treatment of patients with metastatic squamous NSCLC. as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is: Stage III where patients are not candidates for surgicalresection or definitive chemoradiation, or metastatic as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containingchemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. as a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥4 cm), II, or IIIA NSCLC. Malignant Pleural Mesothelioma (MPM) in combination with pemetrexed and platinum chemotherapy, as first-line treatment of adult patients with unresectable advanced or metastatic MPM. Head and Neck Squamous Cell Cancer (HNSCC) in combination with platinum and FU for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. as a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. Classical Hodgkin Lymphoma (cHL) for the treatment of adult patients with relapsed or refractory cHL. for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Primary Mediastinal Large B-Cell Lymphoma (PMBCL) for the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy. Limitations of Use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. Urothelial Cancer in combination with enfortumab vedotin, for the treatment of adult patients with locally advanced or metastatic urothelial cancer. as a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: are not eligible for any platinum-containing chemotherapy, or who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. as a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. Gastric Cancer in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test*. in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma. Esophageal Cancer for the treatment of patients with locally advanced or metastatic esophageal or GEJ tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either: in combination with platinum- and fluoropyrimidine-based chemotherapy, or as a single agent after 1 or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test. Cervical Cancer in combination with chemoradiotherapy, for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. Hepatocellular Carcinoma (HCC) for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen. Biliary Tract Cancer (BTC) in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic BTC. Merkel Cell Carcinoma (MCC) for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC. Renal Cell Carcinoma (RCC) in combination with axitinib, for the first-line treatment of adult patients with advanced RCC. in combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Endometrial Carcinoma in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma. in combination with lenvatinib, for the treatment of adult patients with advanced endometrial carcinoma that is pMMR or not MSI-H as determinedby an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. as a single agent, for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. Cutaneous Squamous Cell Carcinoma (cSCC) for the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. Triple-Negative Breast Cancer (TNBC) for the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. | FoundationOne CDx | KEYNOTE-158NCT02628067 | None |
Abbreviations: ALK = anaplastic lymphoma kinase; CDx = companion diagnostic; CPS = combined positive score; CRC = colorectal cancer; dMMR = mismatch repair-deficient; EC = endometrial cancer; EGFR = epidermal growth factor receptor; FDA = Food and Drug Administration; FIGO = International Federation of Gynecology and Obstetrics; GEJ = gastroesophageal junction; HER-2 = human epidermal growth factor receptor 2; HNSCC = head and neck squamous cell carcinoma; MSI-H = microsatellite instability-high; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand-1; pMMR = mismatch repair-proficient; ROS1 = c-ros oncogene1; TMB = tumor mutational burden; TNBC = triple-negative breast cancer; TPS = tumor proportion score.Source: U.S. Food & Drug Administration (2023).*This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).aCutaneous Melanoma (v.2. 2025)bColon Cancer (v.1.2025)cUterine Neoplasms (v2.2025)dNon-Small Cell Lung Cancer (v3.2025)eHead and Neck Cancers (v2.2025)fEsophageal and Esophagogastric Junction Cancers (v5.2024)gGastric Cancer (v5.2024)hCervical Cancer (v3.2025)iBreast Cancer (v1.2025)jBladder Cancer (v6.2024)
Related medical policies –
Forindividuals with unresectable or metastatic melanoma who receive BRAF V600 gene variant tumor tissue testing to select treatment may be considered medically necessary for U.S. Food and Drug Administration (FDA) approved immune checkpoint inhibitors with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher.
AND
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.
Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations.
For individuals with unresectable or metastatic solid tumors who receive mismatch repair/microsatellite instability tumor tissue testing to select treatment may be considered medically necessary for FDA-approved immune checkpoint inhibitors with NCCN recommendations of 2A or higher.
AND
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.
Analysis of tumor tissue for mismatch repair/microsatellite instability to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations.
For individuals with unresectable or metastatic solid tumors who receive programmed cell death ligand protein-1 (PD-L1) tumor tissue testing to select treatment may be considered medically necessary for FDA-approved immune checkpoint inhibitors with NCCN recommendations of 2A or higher.
AND
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.
PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations.
For individuals with unresectable or metastatic solid tumors who receive tumor mutational burden tumor (TMB) tissue testing to select treatment may be considered medically necessary for FDA-approved immune checkpoint inhibitors with NCCN recommendations of 2A or higher.
AND
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.
TMB testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations. (see Policy Guidelines)
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Testing for individual biomarkers (not panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.
For guidance on testing criteria between policy updates, refer to the FDA's List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) ( https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools ) for an updated list of FDA-approved tumor markers and consult the most current version of NCCN management algorithms.
A number of cancer types have NCCN recommendations of 2A or higher for tumor mutational burden (TMB) testing to identify an FDA-approved therapeutic. No additional evidence outside of what is reviewed in this medical policy appears to have guided those recommendations.
Repeat Genomic Testing
There may be utility in repeated testing of gene variants for determining immunotherapy, as tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for treatment decision-making. The American Society of Clinical Oncology (ASCO) currently suggests repeat genomic testing for individuals on targeted therapy with suspected acquired resistance, especially if choice of next-line therapy would be guided. The ASCO guidance is not tumor specific, and it cautions to consider clinical utility. Refer to NCCN cancer-specific guidelines for guidance.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
appropriate with regard to standards of good medical practice; and
not solely for the convenience of the Member, his or her Provider; and
the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
02/01/2024: New policy added. Approved by the Medical Policy Advisory Committee.
06/03/2024: Policy description updated regarding FDA companion diagnostic tests. Medically necessary policy statement regarding programmed cell death ligand-1 testing updated to include testing for individuals with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. Policy Guidelines updated regarding tumor mutational burden testing and repeat genomic testing.
07/17/2025: Policy description updated regarding immune checkpoint inhibitors and NCCN recommendation levels and guidelines. Policy statements for BRAF V600 Variant Testing, Mismatch Repair/Microsatellite Instability Testing, and Programmed Cell Death Ligand-1 Testing revised and updated to state that testing may be considered medically necessary for FDA-approved immune checkpoint inhibitors with NCCN recommendations of 2A or higher. Policy statement for tumor mutational burden testing to select treatment changed from investigational to medically necessary for FDA-approved immune checkpoint inhibitors with NCCN recommendations of 2A or higher.
10/09/2025: Code Reference section updated to add CPT code 0211U to the Investigational Codes table.
Blue Cross Blue Shield Association policy # 2.04.157
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.
Code Number | Description |
CPT-4 | |
81210 | BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s) |
81301 | Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed |
88341 | Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure) |
88342 | Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure |
88360 | Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; manual |
88361 | Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, per specimen, each single antibody stain procedure; using computer-assisted technology |
81479 | Unlisted molecular pathology procedure |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
Code Number | Description |
CPT-4 | |
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 (FoundationOne CDx™) |
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 (MI Cancer Seek™ – NGS Analysis from Caris) |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.