Coverage Policy Manual
Policy #: 2023023
Category: Laboratory
Initiated: September 2023
Last Review: May 2024
  Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
Description:
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.
 
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 8 FDA-approved immune checkpoint inhibitors:
 
    • Atezolizumab (Tecentriq®)
    • Avelumab (Bavencio®)
    • Cemiplimab (Libtayo®)
    • Dostarlimab-gxly (Jemperli®)
    • Durvalumab (Imfinzi®)
    • Ipilimumab (Yervoy®)
    • Nivolumab (Opdivo®)
    • Pembrolizumab (Keytruda®)
 
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. A complete list of currently available immune checkpoint inhibitors, their labeled indications, and associated companion diagnostic biomarker tests is also included below.
 
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 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 (Vultur, 2011). 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:
 
    • 2015002 Somatic Biomarker testing (including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)
    • 2008027 Somatic Biomarker Testing (including Liquid Biopsy) for Targeted Treatment in Metastatic Colon Cancer (KRAS, NRAS, BRAF, and HER)
    • 2011061 Genetic Test: Melanoma and Glioma, Testing to Predict Response to Targeted Therapy
 
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 (Bonneville, 2020).
 
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 (Merino, 2020).
 
Regulatory Status
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.
 
Below is a summary of the 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: BRAF V600
Immune Checkpoint Inhibitor: Atezolizumab (Tecentriq®) + cobimetinib (Cotellic®) + vemurafenib (Zelboraf®)
Indication: Patients with BRAF V600 mutation-positive unresectable or metastatic melanoma
Companion Test: FoundationOne CDx
Pivotal Studies: IMspire150 NCT02908672 (Gutzmer, 2020)
 
Biomarker: dMMR/MSI-H
Immune Checkpoint Inhibitor: Nivolumab (Opdivo®) +/- Ipilimumab (Yervoy®)
Indication: Patients 12 years of age and older with dMMR or MSI-H metastatic colorectal cancer that has progressed following treatment, as a single agent or in combination with ipilimumab
Companion Test: None
Pivotal Studies: CHECKMATE-142 NCT02060188 (Lenz, 2022)
 
Biomarker: dMMR/MSI-H
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda®)
Indication: 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
Companion Test: Ventana MMR RxDx (dMMR) and FoundationOne CDx (MSI-H)
Pivotal Studies: KEYNOTE-158 NCT02628067 (Marabelle, 2020)
 
Biomarker: dMMR/MSI-H
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: Patients with unresectable or metastatic MSI-H or dMMR CRC as determined by an FDA-approved test
Companion Test: None
Pivotal Studies: KEYNOTE-177 NCT02563002 (Andre, 2020; Diaz, 2022)
 
Biomarker: pMMR/ MSI-H
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda) + Lenvatinib (Lenmiva®)
Indication: 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
Companion Test: Ventana MMR RxDx
Pivotal Studies: KEYNOTE-775 NCT03517449 (Makker, 2022)
 
Biomarker: dMMR
Immune Checkpoint Inhibitor: Dostarlimab (Jemperli®)
Indication: 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
Companion Test: Ventana MMR RxDx Panel
Pivotal Studies: GARNET NCT02715284 (Oaknin, 2020)
 
Biomarker: dMMR
Immune Checkpoint Inhibitor: Dostarlimab (Jemperli)
Indication: 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
Companion Test: Ventana MMR RxDx Panel
Pivotal Studies: RUBY NCT03981796 (Mirza, 2023)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: 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
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: KEYNOTE-024 NCT02142738 (Reck, 2016)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: First-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 as determined by an FDA-approved test
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: KEYNOTE-048 NCT05252429 (Burtness, 2019)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: 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
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: KEYNOTE-590 NCT03881111 (Sun, 2021)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: 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 or more) as determined by an FDA-approved test.
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: KEYNOTE-811 NCT03615326 (Janjigian, 2021)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: In combination with chemotherapy, with or without bevacizumab, patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1 or more) 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 or more) as determined by an FDA-approved test
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: KEYNOTE-826 NCT03635567 (Colombo, 2021)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: In combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or more) as determined by an FDA approved test
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: KEYNOTE-355 NCT02819518 (Cortes, 2022)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Cemiplimab (Libtayo®)
Indication: First-line treatment of adult patients with NSCLC whose tumors have high PD-L1 expression (TPS 50% or greater) 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
Companion Test: PD-L1 IHC 22C3 pharmDx
Pivotal Studies: EMPOWER-Lung 1 NCT03088540 (Sezer, 2021)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Nivolumab (Opdivo) + Ipilimumab (Yervoy)
Indication: Patients with metastatic NSCLC expressing PD-L1 as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations
Companion Test: PD-L1 IHC 28-8 pharmDx
Pivotal Studies: CHECKMATE-227 NCT02477826 (Hellmann, 2019)
 
Biomarker: PD-L1
Immune Checkpoint Inhibitor: Atezolizumab (Tecentriq)
Indication: 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
Companion Test: Ventana PD-L1 (SP263) Assay
Pivotal Studies: NCT02409342 (Herbst, 2020)
 
Biomarker: TMB
Immune Checkpoint Inhibitor: Pembrolizumab (Keytruda)
Indication: 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
Companion Test: FoundationOne CDx
Pivotal Studies: KEYNOTE-158 NCT02628067 (Marabelle, 2020)
 
Source: U.S. Food & Drug Administration (U.S. FDA, 2023; U.S. FDA, 2023).
Policy/
Coverage:
Effective June 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
BRAF V600 variant testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
 
    • Individuals with unresectable or metastatic melanoma
 
AND
 
    • The individual does not have any U.S. Food and Drug Administration (FDA)-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
 
Mismatch repair/microsatellite instability (MMR/MSI) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
 
    • Individuals with advanced or metastatic colorectal cancer; OR
    • Individuals with advanced endometrial carcinoma who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation; OR
    • Individuals with unresectable or metastatic solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.
 
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.
 
Programmed cell death ligand protein-1 (PD-L1) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
 
    • Individuals with metastatic non-small cell lung cancer (NSCLC); OR
    • Individuals with metastatic or unresectable, recurrent head and neck squamous cell carcinomas; OR
    • 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 prior lines of systemic therapy for patients with tumors of squamous cell histology; OR
    • Individuals with persistent, recurrent, or metastatic cervical cancer; OR
    • Individuals with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma OR
    • Individuals with locally recurrent unresectable or metastatic hormone receptor-negative/HER2-negative (triple negative) breast cancer.
 
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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.in all other situations.
 
For members with contracts without primary coverage criteria, mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.in all other situations.
 
For members with contracts without primary coverage criteria, PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective September 15, 2023 – May 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
BRAF V600 variant testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
 
    • Individuals with unresectable or metastatic melanoma
AND
    • The individual does not have any U.S. Food and Drug Administration (FDA)-labeled contraindications to the requested agent and the agent is intended to be used consistently with the FDA-approved label.
 
Mismatch repair/microsatellite instability (MMR/MSI) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
 
    • Individuals with advanced or metastatic colorectal cancer; OR
    • Individuals with advanced endometrial carcinoma who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation; OR
    • Individuals with unresectable or metastatic solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.
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.
 
Programmed cell death ligand protein-1 (PD-L1) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following circumstances:
 
    • Individuals with metastatic non-small cell lung cancer (NSCLC); OR
    • Individuals with metastatic or unresectable, recurrent head and neck squamous cell carcinomas; OR
    • 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 prior lines of systemic therapy for patients with tumors of squamous cell histology; OR
    • Individuals with persistent, recurrent, or metastatic cervical cancer; OR
    • Individuals with locally recurrent unresectable or metastatic hormone receptor-negative/HER2-negative (triple negative) breast cancer.
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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, analysis of tumor tissue for the somatic BRAF V600 variant to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.in all other situations.
 
For members with contracts without primary coverage criteria, mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.in all other situations.
 
For members with contracts without primary coverage criteria, PD-L1 testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all other situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations not addressed in this or other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy in all situations not addressed in this or other policies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
This evidence review was created in April 2023 with a search of the PubMed database. The most recent literature update was performed through March 26, 2023.
 
Somatic Testing for the BRAF V600E Variant to Guide Immune Checkpoint Inhibitor Therapy
Gutzmer et al reported primary results from IMspire150, a phase 3, double-blind, randomized controlled trial (RCT) of atezolizumab, vemurafenib, and cobimetinib (n=256) compared to placebo, vemurafenib, and cobimetinib (n=258) as first-line treatment for unresectable advanced BRAF V600-positive melanoma (Gutzmer, 2020). The primary endpoint was investigator-assessed PFS. The median follow-up in the overall study population was 18.9 months. At data cut-off, 327 patients had progressive disease by investigator assessment or had died, including 148 (58%) patients in the atezolizumab group and 179 (69%) in the control group. The atezolizumab with vemurafenib and cobimetinib group experienced a median PFS per investigator assessment of 15.1 months (95% confidence interval [CI], 0.63 to 0.97) compared to 10.6 months (95% CI, 9.3 to 12.7) in the control group (hazard ratio [HR], 0.78; 95% CI, 0.63 to 0 97; p=.025).
 
Based on clinical trial results, testing for the BRAF V600E variant in individuals with unresectable or metastatic melanoma for determining treatment with atezolizumab in combination with cobimetinib and vemurafenib has received FDA approval and an NCCN recommendation.
 
Microsatellite Instability High/Mismatch Repair Deficient Testing to Guide Immune Checkpoint Inhibitor Therapy
Evidence for the effectiveness of pembrolizumab in patients with MSI-high/MMR-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC) comes from the KEYNOTE-177 trial, reported by Andre et al (Andre, 2020). The trial demonstrated a statistically significant improvement in PFS for patients randomized to pembrolizumab compared with chemotherapy (HR, 0.60; 95% CI, 0.45 to 0.80; p=.0002). Final results were reported by Diaz et al (Diaz, 2022). Median PFS was 16.5 months (95% CI, 5.4 to 38.1) with pembrolizumab versus 8.2 months (6.1 to 10.2) with chemotherapy (HR, 0.59; 95% CI 0.45 to 0.79). Treatment-related adverse events of grade 3 or worse occurred in 33 of 153 (22%) patients in the pembrolizumab group versus 95 of 143 (66%) patients in the chemotherapy group.
 
The FDA approval for pembrolizumab in advanced endometrial cancer that is MMR proficient was based on the KEYNOTE-775 phase 3 trial, reported by Makker et al (Makker, 2022).
 
The FDA approval for dostarlimab for dMMR recurrent or advanced endometrial cancer was based on the nonrandomized, phase 1, GARNET trial (NCT02715284, N=104), reported by Oaknin et al (Oaknin, 2020). At a median follow-up of 11.2 months, the confirmed objective response rate was 42%; 13% of patients had a confirmed complete response, and 30% of patients had a confirmed partial response.
 
Two additional phase 3 RCTs of immune checkpoint inhibitor therapy for endometrial cancer indications that do not yet have FDA approval were published in March 2023 and are discussed below.
 
Mirza et al reported on a trial of dostarlimab plus carboplatin-paclitaxel among patients with primary advanced or recurrent endometrial cancer (Mirza, 2023). Of the 494 patients who underwent randomization, 118 (23.9%) had dMMR, MSI-H tumors. In the dMMR, MSI-H population, estimated PFS at 24 months was 61.4% (95% CI, 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (HR for progression or death, 0.28; 95% CI, 0.16 to 0.50; p<.001). In the overall population, PFS at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (HR, 0.64; 95% CI, 0.51 to 0.80; p<.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (HR for death, 0.64; 95% CI, 0.46 to 0.87).
 
Eskander et al reported on a phase 3 RCT of the addition of pembrolizumab to standard chemotherapy in individuals with advanced or recurrent endometrial cancer (Eskander, 2023). Participants were stratified into 2 cohorts according to whether they had dMMR or mismatch repair-proficient (pMMR) disease. In the 12-month analysis, PFS in the dMMR cohort was 74% in the pembrolizumab group and 38% in the placebo group (HR for progression or death, 0.30; 95% CI 0.19 to 0.48; p<.001). In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (HR 0.54; 95% CI, 0.41 to 0.71; p<.001).
 
The FDA approval of pembrolizumab in individuals with dMMR or MSI-H solid tumors was supported by the phase 2 KEYNOTE-158 study, reported by Marabelle et al (Marabelle, 2020). The trial included a total of 233 previously treated participants with MSI-H solid tumors. The objective response rate (ORR) was 34.3% (95% CI, 28.3 to 40.8). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median OS was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%).
 
Based on clinical trial data, MSI/MMR testing has received FDA approval and NCCN recommendations to select immune checkpoint inhibitor therapy in individuals with advanced or metastatic CRC, individuals with advanced endometrial carcinoma, and individuals with unresectable or metastatic solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.
 
Programmed Cell Death Ligand Protein-1 Testing to Guide Immune Checkpoint Inhibitor Therapy
In RCTs, individuals with high PD-L1 expression had longer PFS and fewer adverse events when treated with anti-PD-L1 monoclonal antibodies than with platinum chemotherapy. In the KEYNOTE trial, first-line treatment with nivolumab plus ipilimumab resulted in a longer duration of OS than did chemotherapy in patients with non-small cell lung cancer (NSCLC), independent of the PD-L1 expression level.
 
The EMPOWER-Lung 1 trial (NCT03088540) was a multicenter, open-label trial that randomized 710 patients 1:1 to receive either cemiplimab-rwlc or platinum-based chemotherapy (Sezer, 2021). Median OS was 22.1 months (95% CI, 17.7 to not estimable) in the cemiplimab-rwlc arm compared to 14.3 months (95% CI, 11.7 to 19.2) in the chemotherapy arm (HR, 0.68; 95% CI, 0.53 to 0.87; p=.0022). Median PFS was 6.2 months with cemiplimab-rwlc versus 5.6 months with chemotherapy (HR, 0.59; 95% CI, 0.49 to 0.72; p<.0001). Corresponding ORRs were 37% (95% CI, 32 to 42) versus 21% (95% CI, 17 to 25), respectively. The most common adverse events were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough.
 
Herbst et al published results of a phase 3, open label RCT of atezolizumab compared to platinum-based chemotherapy in 572 patients with NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells (NCT02409342) (Herbst, 2020). In the subgroup of patients with tumors who had the highest expression of PD-L1 (205 patients), the median OS was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; HR for death, 0.59; p=.01). Atezolizumab treatment resulted in significantly longer OS than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. Grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the atezolizumab group and the chemotherapy group, respectively.
 
Reck et al published results of the KEYNOTE-024 Trial (NCT02142738), which compared pembrolizumab to platinum-based chemotherapy in 305 patients with NSCLC and PD-L1 expression on at least 50% of tumor cells (Reck, 2016). At a median follow-up of 11.2 months, PFS was longer with pembrolizumab compared with chemotherapy (median PFS, 10.3 vs. 6 months; HR, 0.50; 95% CI, 0.37 to 0.68). The median duration of response was not reached in the pembrolizumab group and was 6.3 months in the chemotherapy group.
 
In the CHECKMATE-227 trial (NCT02477826) reported by Hellmann et al, among the patients with a PD-L1 expression level of 1% or more, the median duration of OS was 17.1 months (95% CI, 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (p=.007), with 2-year OS rates of 40.0% and 32.8%, respectively (Hellmann, 2019). The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of OS than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level.
 
The FDA approval of pembrolizumab for head and neck squamous cell carcinoma was based on the KEYNOTE-048 trial of pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy (Burtness, 2019).
 
The FDA approval of pembrolizumab monotherapy for individuals with esophageal cancer of squamous cell etiology that express PD-L1 was based on the placebo-controlled, phase 3 KEYNOTE-590 trial (Sun, 2021).
 
The FDA approval of pembrolizumab for individuals with persistent, recurrent, or metastatic cervical cancer was based on the phase 3 KEYNOTE-826 trial (Colombo, 2021).
 
The efficacy of pembrolizumab plus chemotherapy compared to placebo plus chemotherapy for previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (N=847) was evaluated in the KEYNOTE-355 study. Dual primary efficacy endpoints were PFS and overall survival in patients with PD-L1 combined positive score of at least 1. Interim study results were published in 2020, and final results were published in 2022 (Cortes, 2020; Cortes, 2022). This study formed the basis of pembrolizumab accelerated approval in patients with unresectable or metastatic triple-negative breast cancer and PD-L1 combined positive score (CPS) of at least 10. Two nonrandomized trials of pembrolizumab for patients with PD-L1 positive triple negative breast cancer reported objective response rates of 21.4% (95% CI, 13.9 to 31.4) and 18.5% (95% CI, 6.3 to 38.1) (Adams, 2019; Nanda, 2016).
 
In December 2022, Genentech voluntarily withdrew its accelerated approval for atezolizumab for the treatment of urothelial carcinoma after its required follow-up trial did not demonstrate improved OS for atezolizumab plus chemotherapy compared with chemotherapy alone (Medscape Medical News, 2022).
 
Based on clinical trial data, PD-L1 testing has received FDA approval and NCCN recommendations to select immune checkpoint inhibitor therapy in individuals with metastatic NSCLC; individuals with metastatic or unresectable, recurrent head and neck squamous cell carcinomas; individuals with locally advanced or metastatic esophageal or gastroesophageal junction carcinoma; individuals with persistent, recurrent, or metastatic cervical cancer; and individuals with locally recurrent unresectable or metastatic triple negative breast cancer.
 
Tumor Mutational Burden Testing to Guide Immune Checkpoint Inhibitor Therapy
Marabelle et al reported the association of high TMB to response to pembrolizumab in patients with solid tumors enrolled in a prespecified exploratory analysis of the KEYNOTE-158 study (Marabelle, 2020). High TMB was defined as more than 10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the tissue TMB (tTMB)-high group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the tTMB-high group and was 33.1 months in the non-tTMB-high group. Notably, TMB-high status was associated with improved response irrespective of PD-L1. Median PFS and OS did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI, 24 to 48) of 68 participants who had both tTMB-high status and PD-L1-positive tumors (i.e., PD-L1 combined positive score of ≥1) and in 6 (21%; 95% CI, 8 to 40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. The KEYNOTE-158 nonrandomized phase 2 trial examined pembrolizumab; objective responses were observed in 35% of participants who had both TMB-high status and PD-L1-positive tumors and in 21% of participants who had TMB-high status and PD-L1-negative tumors. High TMB status was associated with improved response irrespective of PD-L1 status. Median OS and PFS were not significantly different between TMB groups.
 
In a prespecified subgroup analysis of a nonrandomized trial of pembrolizumab in individuals with various solid tumors, objective responses were observed in 24 (35%; 95% CI, 24 to 48) of 68 participants who had both tTMB-high status and PD-L1-positive tumors and in 6 (21%; 95% CI, 8 to 40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. High TMB status was associated with improved response irrespective of PD-L1 status. Median OS and progression-free survival were not significantly different between TMB groups. In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and OS in patients receiving immunotherapy.
 
American Society of Clinical Oncology
Solid Tumors
In 2022, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion (PCO) on the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors (Chakravarty, 2022). The opinion notes the following:
 
PCO 1.1. Genomic testing should be performed for patients with metastatic or advanced solid tumors with adequate performance status in the following 2 clinical scenarios:
 
    • When there are genomic biomarker-linked therapies approved by regulatory agencies for their cancer.
    • When considering a treatment for which there are specific genomic biomarker-based contraindications or exclusions (strength of recommendation: strong).
 
PCO 1.2.1. For patients with metastatic or advanced solid tumors, genomic testing using multigene genomic sequencing is preferred whenever patients are eligible for a genomic biomarker-linked therapy that a regulatory agency has approved (strength of recommendation: moderate).
PCO 1.2.2. Multigene panel-based genomic testing should be used whenever more than one genomic biomarker is linked to a regulatory agency-approved therapy (strength of recommendation: strong).
PCO 2.1. Mismatch repair deficiency (dMMR) status should be evaluated on patients with metastatic or advanced solid tumors who are candidates for immunotherapy. There are multiple approaches, including using large multigene panel-based testing to assess microsatellite instability (MSI). Consider the prevalence of dMMR and/or MSI-high (MSI-H) status in individual tumor types when making this decision (strength of recommendation: strong).
PCO 2.2. When tumor mutational burden (TMB) may influence the decision to use immunotherapy, testing should be performed with either large multigene panels with validated TMB testing or whole-exome analysis (strength of recommendation: strong).
PCO 4.1. Genomic testing should be considered to determine candidacy for tumor-agnostic therapies in patients with metastatic or advanced solid tumors without approved genomic biomarker–linked therapies (strength of recommendation: moderate).
 
Head and Neck Cancers
In 2023, the ASCO released a guideline on immunotherapy and biomarker testing in recurrent and metastatic head and neck cancers (Yilmaz, 2023). The guideline included a recommendation for programmed cell death ligand protein-1 (PD-L1) testing for individuals with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), and a consideration for TMB testing for individuals with recurrent or metastatic disease when the PD-L1 combined positive score is not available or in individuals with rare tumors.
 
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) cancer-specific guidelines provide recommendations for biomarkers that should be tested to guide decisions about immune checkpoint inhibitor therapy and recommend testing techniques. Guidelines are updated frequently; refer to the source documents for current recommendations. The following NCCN guidelines were used to inform this evidence opinion:
 
    • Bladder Cancer (v.1.2023) (NCCN, 2023)
    • Breast Cancer (v.4.2023) (NCCN, 2023)
    • Cervical Cancer (v.1.2023) (NCCN, 2023)
    • Colon Cancer. (v.1.2023) (NCCN, 2023)
    • Esophageal and Esophagogastric Junction Cancers (v.2.2023) (NCCN, 2023)
    • Head and Neck Cancers. (v.1.2023) (NCCN, 2023)
    • Melanoma: Cutaneous. (v.2.2023) (NCCN, 2023)
    • Non-Small Cell Lung Cancer. (v..2.2023) (NCCN, 2023)
    • Uterine Neoplasms. (v.1.2023) (NCCN, 2023)
 
Ongoing and Unpublished Clinical Trials
Some currently ongoing trials that might influence this review are listed below:
  • NCT04949113 Multicenter Phase 3 Trial Comparing Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma – NADINA has a planned enrollment of 420 and a planned completion date of January 2027
  • NCT05727904 A Phase 3, Multicenter, Randomized, Open-label, Parallel Group, Treatment Study to Assess the Efficacy and Safety of the Lifileucel (LN-144, Autologous Tumor Infiltrating Lymphocytes [TIL]) Regimen in Combination With Pembrolizumab Compared With Pembrolizumab Monotherapy in Participants With Untreated, Unresectable or Metastatic Melanoma has a planned enrollment of 670 and a planned completion date of March 2030
  • NCT05722886 DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations has a planned enrollment of 825 and a planned completion date of October 2029
  • NCT04008030 A Phase 3 Randomized Clinical Trial of Nivolumab Alone, Nivolumab in Combination With Ipilimumab, or Investigator's Choice Chemotherapy in Participants With Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer has a planned enrollment of 831 and a planned completion date of Jun 2026
  • NCT05328908 A Phase 3, Randomized, Open-label Study of Relatlimab-nivolumab Fixed-dose Combination Versus Regorafenib or Trifluridine + Tipiracil (TAS-102) for Participants With Later-lines of Metastatic Colorectal Cancer has a planned enrollment of 700 and a planned completion date of May 2028
  • NCT04674683 A Multicenter, Randomized, Double-Blind Phase 3 Study of HBI-8000 Combined With Nivolumab Versus Placebo With Nivolumab in Patients With Unresectable or Metastatic Melanoma Not Previously Treated With PD-1 or PD-L1Inhibitors has a planned enrollment of 480 and a planned completion date of Oct 2025
  • NCT04334759 DREAM3R: DuRvalumab (MEDI4736) With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma - A Phase 3 Randomised Trial has a planned enrollment of 480 and a planned completion date of December 2025
  • NCT05328908 A Phase 3, Randomized, Open-label Study of Relatlimab-nivolumab Fixed-dose Combination Versus Regorafenib or Trifluridine + Tipiracil (TAS-102) for Participants With Later-lines of Metastatic Colorectal Cancer has a planned enrollment of 700 and a planned completion date of May 2028
  • NCT03036098 A Phase 3, Open-label, Randomized Study of Nivolumab Combined With Ipilimumab, or With Standard of Care Chemotherapy, Versus Standard of Care Chemotherapy in Participants With Previously Untreated Unresectable or Metastatic Urothelial Cancer has a planned enrollment of 1307 and a planned completion date of July 2025
  • NCT03811015 A Phase III Randomized Study of Maintenance Nivolumab Versus Observation in Patients With Locally Advanced, Intermediate Risk HPV Positive OPSCC has a planned enrollment of 636 and a planned completion date of January 2027
  • NCT03366272 Improvement of Outcome in Elderly Patients or Patients Not Eligible for High-dose Chemotherapy With Aggressive NHL in First Relapse/Progression by Adding Nivolumab to Gemcitabine, Oxaliplatin Plus Rituximab in Case of B-cell Lymphoma has a planned enrollment of 388 and a planned completion date of November 2024
  • NCT05677490 Randomized Phase III Trial of mFOLFIRINOX vs. FOLFOX With Nivolumab for First-Line Treatment of Metastatic HER2- Gastroesophageal Adenocarcinoma has a planned enrollment of 382 and a planned completion date of November 2028
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
0037UTargeted 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
81210BRAF (B Raf proto oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
81301Microsatellite 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
81479Unlisted molecular pathology procedure
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Mirza MR, Chase DM, Slomovitz BM, et al.(2023) Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

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