Medical Policy

Policy Num:      11.003.140
Policy Name:    Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
Policy ID:          [11.003.140]  [Ac / B / M+ / P+]  [2.04.157]

Last Review:      May 12, 2024
Next Review:     May 20, 2025
 

Related Policies:

11.003.135 - Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer
11.003.138 - Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, Microsatellite Instability/Mismatch Repair, Tumor Mutational Burden)
11.003.139 - Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, Tumor Mutational Burden, Microsatellite Instability/Mismatch Repair)
11.003.009 - 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)
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, MMR/MSI, HER2, and TMB)
11.003.011 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy or Immunotherapy
05.001.034 - Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)

Summary

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.

Summary of Evidence

For individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy who receive somatic testing for BRAF V600 variants, the evidence includes a placebo-controlled phase 3 randomized controlled trial (RCT) of atezolizumab in individuals with unresectable advanced BRAF V600-positive melanoma. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, and treatment-related morbidity. In the IMspire150 trial, participants who received atezolizumab with vemurafenib and cobimetinib (n=256) experienced a median progression-free survival (PFS) of 15.1 months compared to 10.6 months in the control group of placebo, vemurafenib, and cobimetinib (n=258) (hazard ratio, 0.78; 95% confidence interval [CI], 0.63 to 0 97; p=.025). Based on these 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 U.S. Food and Drug Administration (FDA) approval and a National Comprehensive Cancer Network (NCCN) recommendation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy who receive mismatch repair/microsatellite instability (MMR/MSI) testing, the evidence includes RCTs and nonrandomized trials. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. 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 colorectal cancer, 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. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy who receive somatic testing for programmed cell death ligand protein-1 (PD-L1) variants, the evidence includes RCTs and nonrandomized trials. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. 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 non-small cell lung cancer; 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; individuals with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma; and individuals with locally recurrent unresectable or metastatic triple negative breast cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with cancer who receive tumor mutational burden (TMB) testing to select treatment with immune checkpoint inhibitors, the evidence includes prospective and retrospective subgroup analyses of nonrandomized trials. Relevant outcomes include OS, disease-specific survival, test validity, quality of life, and treatment-related morbidity. 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 tissue TMB (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 PFS were not significantly different between TMB groups. In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and overall survival in patients receiving immunotherapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether using somatic biomarker testing improves the net health outcome in individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy.

POLICY

BRAF V600 Variant Testing

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

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.

Mismatch Repair/Microsatellite Instability Testing

Mismatch repair/microsatellite instability (MMR/MSI) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy may be considered medically necessary 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.

Mismatch repair/microsatellite instability testing to select individuals for immune checkpoint inhibitor therapy is considered investigational in all other situations.

Programmed Cell Death Ligand-1 Testing

Programmed cell death ligand protein-1 (PD-L1) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy may be considered medically necessary 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.

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

Tumor Mutational Burden Testing

Tumor mutational burden (TMB) testing of tumor tissue to select individuals for immune checkpoint inhibitor therapy is considered investigational (see Policy Guidelines).

POLICY GUIDELINES

This policy does not address neurotrophic tyrosine receptor kinase (NTRK) testing. The use of tropomyosin receptor kinase (TRK) inhibitors for individuals with NTRK gene fusion-positive solid tumors is addressed separately in evidence review 05.001.034

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 reference 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 (Chakravarty et al, 2022; PMID 35175857). Refer to NCCN cancer-specific guidelines for guidance.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

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. Refer to Table 1 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 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.^1, 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 evidence opinion (e.g., to select individuals for targeted treatment with BRAF or MEK inhibitors); refer to the following related policies:

• 11.003.009 - 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): BRAF testing for BRAF inhibitors in NSCLC

• 11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, MMR/MSI, HER2, and TMB)

• 11.003.011 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy or Immunotherapy

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..^2,

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.^3,

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.

Table 1 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.

Table 1. FDA Companion Diagnostic Tests for Immune Checkpoint Inhibitor Therapy

BRAFAbbreviations: ALK, anaplastic lymphoma kinase; CPS, combined positive score; CRC, colorectal cancer; dMMR, mismatch repair-deficient; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; HNSCC, head and neck squamous cell carcinoma; MSI-H, microsatellite instability-high; NSCLC, non-small cell lung cancer; pMMR, mismatch repair-proficient; ROS1, c-ros oncogene1; TNBC, triple-negative breast cancer; TMB, tumor mutational burden; TPS, tumor proportion score.
Source: U.S. Food & Drug Administration (2023).^22,;^23,
*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). 

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 8, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Somatic Testing for the BRAF V600E Variant to Guide Immune Checkpoint Inhibitor Therapy

Clinical Context and Test Purpose

The purpose of somatic testing for the BRAF V600 variant in individuals who have cancer is to inform a decision about immune checkpoint inhibitor therapy.

The following PICO was used to select literature to inform this review.

Population

The relevant population of interest is individuals with cancer who are being considered for immune checkpoint inhibitor therapy.

Intervention

The therapy being considered is somatic testing for the BRAF V600E variant.

Comparator

The comparator of interest is standard treatment without BRAF variant testing.

Outcomes

The primary outcomes of interest are overall survival (OS) and progression-free survival (PFS). False-positive BRAF test results could lead to inappropriate treatment with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, which have not been shown to be effective in patients without BRAF V600 pathogenic variants, and also could lead to delay in treatment with immunotherapy.

Study Selection Criteria

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.

Review of Evidence

Melanoma

Gutzmer et al (2020) 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.^4, 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).

Section Summary: Somatic Testing for BRAF Variants to Guide Immune Checkpoint Inhibitor Therapy

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.

For individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy who receive somatic testing for BRAF V600 variants, the evidence includes a placebo-controlled phase 3 randomized controlled trial (RCT) of atezolizumab in individuals with unresectable advanced BRAF V600-positive melanoma. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, and treatment-related morbidity. In the IMspire150 trial, participants who received atezolizumab with vemurafenib and cobimetinib (n=256) experienced a median progression-free survival (PFS) of 15.1 months compared to 10.6 months in the control group of placebo, vemurafenib, and cobimetinib (n=258) (hazard ratio, 0.78; 95% confidence interval [CI], 0.63 to 0 97; p=.025). Based on these 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 U.S. Food and Drug Administration (FDA) approval and a National Comprehensive Cancer Network (NCCN) recommendation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Microsatellite Instability High/Mismatch Repair Deficient Testing to Guide Immune Checkpoint Inhibitor Therapy

Clinical Context and Test Purpose

The purpose of microsatellite instability/mismatch repair (MSI/MMR) testing in individuals who have cancer is to inform a decision about immune checkpoint inhibitor therapy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with cancer who are being considered for immune checkpoint inhibitor therapy.

Interventions

The test being considered is MSI/MMR testing.

Comparator

The comparator of interest is standard treatment without MSI/MMR testing.

Outcomes

The primary outcomes of interest are OS and PFS.

Study Selection Criteria

Testing for individual biomarkers (not panels) associated with FDA-approved therapeutics (ie, as companion diagnostic tests) for therapies with 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.

Review of Evidence

Colorectal Cancer

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 (2020).^7, 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 (2022).^8, 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.

Endometrial Cancer

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 (2022).^9,

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 (2020).^10, 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 (2023) reported on a trial of dostarlimab plus carboplatin-paclitaxel among patients with primary advanced or recurrent endometrial cancer.^11, 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 (2023) reported on a phase 3 RCT of the addition of pembrolizumab to standard chemotherapy in individuals with advanced or recurrent endometrial cancer.^24, 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).

Solid Tumors

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 (2020).^6, The trial included a total of 233 previously treated participants with MSI-H solid tumors. The 7 tumor types with the greatest enrollment were endometrial (n=49), gastric (n=24), cholangiocarcinoma (n=22), pancreatic (n=22), small intestine (n=19), ovarian (n=15), and brain (n=13). 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%).

Section Summary: Microsatellite Instability High/Mismatch Repair Deficient Testing to Guide Immune Checkpoint Inhibitor Therapy

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.

For individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy who receive mismatch repair/microsatellite instability (MMR/MSI) testing, the evidence includes RCTs and nonrandomized trials. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. 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 colorectal cancer, 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. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Programmed Cell Death Ligand Protein-1 Testing to Guide Immune Checkpoint Inhibitor Therapy

The purpose of programmed cell death ligand protein-1 (PD-L1) testing in individuals who have cancer is to inform a decision about immune checkpoint inhibitor therapy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with cancer who are being considered for immune checkpoint inhibitor therapy.

Interventions

The intervention of interest is testing for PD-L1.

The purpose of identifying PD-L1 expression is to inform a decision whether patients should receive a immunotherapy versus another systemic therapy. Patients who present with advanced disease or recurrence following initial definitive treatment typically receive systemic therapy. Traditionally, systemic therapy was cytotoxic chemotherapy. Targeted treatments are ineffective in patients whose tumors lack genetic alterations such as EGFR, ALK, BRAF, and ROS1 variants (driver mutations). However, a subset of these patients may be good candidates for treatment with immunotherapy. The goal of immunotherapy is to preferentially kill malignant cells without significant damage to normal cells so that there is improved therapeutic efficacy along with decreased toxicity.

Comparators

The comparator of interest is standard management without testing for PD-L1. Standard management consists primarily of chemotherapy.

Outcomes

Beneficial outcomes resulting from a true-positive test result are prolonged survival, reduced toxicity, and improved quality of life (QOL) associated with receiving a more effective and less cytotoxic targeted therapy than chemotherapy. The beneficial outcome from a true negative result is prolonged survival associated with receiving chemotherapy in those whose tumors do not express PD-L1.

Harmful outcomes resulting from a false-negative test result include shorter survival from receiving less effective and more cytotoxic chemotherapy in those whose tumors express PD-L1; possible harmful outcomes resulting from a false-positive test result are a shorter survival from receiving potentially ineffective immunotherapy and delay in initiation of chemotherapy in those whose tumors do not express PD-L1.

The duration of follow-up for the outcomes of interest is 6 months to 1 year.

Study Selection Criteria

Testing for individual biomarkers (not panels) associated with FDA-approved therapeutics (ie, as companion diagnostic tests) for therapies with 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.

Review of Evidence

Non-Small Cell Lung Cancer

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.^18, 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 (2020) 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).^20, 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 (2016) 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.^12, 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 (2019), 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.^19, 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.

Head and Neck Squamous Cell Carcinoma

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.^13,

Esophageal Cancer

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.^14,

Cervical Cancer

The FDA approval of pembrolizumab for individuals with persistent, recurrent, or metastatic cervical cancer was based on the phase 3 KEYNOTE-826 trial.^16,

Gastric Cancer

The FDA approval of pembrolizumab for individuals with gastric or gastroesophageal junction adenocarcinoma was based on the KEYNOTE-811 trial.^15,

Triple Negative Breast Cancer

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,^25, and final results were published in 2022.^17, 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).^26,27,

Urothelial Carcinoma

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.^28,

Section Summary: Programmed Cell Death Ligand Protein-1 Testing to Guide Immune Checkpoint Inhibitor Therapy

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.

For individuals with cancer who are being evaluated for immune checkpoint inhibitor therapy who receive somatic testing for programmed cell death ligand protein-1 (PD-L1) variants, the evidence includes RCTs and nonrandomized trials. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. 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 non-small cell lung cancer; 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; individuals with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma; and individuals with locally recurrent unresectable or metastatic triple negative breast cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Tumor Mutational Burden Testing to Guide Immune Checkpoint Inhibitor Therapy

Clinical Context and Test Purpose

The purpose of somatic tumor mutational burden (TMB) testing in individuals who have cancer is to inform a decision about immune checkpoint inhibitor therapy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with cancer.

Interventions

The therapy being considered is TMB testing.

Comparators

Outcomes

The general outcomes of interest are OS and PFS.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Marabelle et al (2020) 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.^21, 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 (ie, 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.

Section Summary: Tumor Mutational Burden Testing to Guide Immune Checkpoint Inhibitor Therapy

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.

For individuals with cancer who receive tumor mutational burden (TMB) testing to select treatment with immune checkpoint inhibitors, the evidence includes prospective and retrospective subgroup analyses of nonrandomized trials. Relevant outcomes include OS, disease-specific survival, test validity, quality of life, and treatment-related morbidity. 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 tissue TMB (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 PFS were not significantly different between TMB groups. In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and overall survival in patients receiving immunotherapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

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.^29, 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.^30, 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 reucrrent 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. 2.2024)^31,

• Breast Cancer (v. 2.2024)^32,

• Cervical Cancer (v. 2.2024)^33,

• Colon Cancer. (v. 1.2024)^34,

• Esophageal and Esophagogastric Junction Cancers (v. 1.2024)^35,

• Gastric Cancer (v.1.2024)^36,

• Head and Neck Cancers. (v. 2.2024)^37,

• Melanoma: Cutaneous. (v. 1.2024)^38,

• Non-Small Cell Lung Cancer. (v. 3.2024)^39,

• Uterine Neoplasms. (v. 2.2024)^40,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Ongoing Trials

NCT: national clinical trial.

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Codes

Policy History