Medical Policy

Policy Num:      11.003.004
Policy Name:    Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)
Policy ID:          [11.003.004]  [Ac / B / M+ / P+]  [2.04.53]

Last Review:     August 23, 2024
Next Review:    August 20, 2025
 

Related Policies:

11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.003.026 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.015 - Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer
05.001.034 - Tropomyosin Receptor Kinase Inhibitors for Locally Advanced or Metastatic Solid Tumors Harboring an NTRK Gene Fusion

Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)

SUMMARY

Summary

Description

The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC). EGFR-targeted therapy combined with monoclonal antibodies cetuximab and panitumumab has shown a clear survival benefit in patients with metastatic CRC. However, this benefit depends on a lack of variants in certain genes in the signaling pathway downstream from the EGFR. It has been hypothesized that knowledge of tumor cell KRAS, NRAS, BRAF variant status might be used to predict nonresponse to anti-EGFR monoclonal antibody therapy. NTRK gene fusions, which are rare kinase fusion events, are a potential therapeutic target for CRC patients who may benefit from tropomysosin receptor kinase (TRK) inhibitor therapy. More recently, human epidermal growth factor receptor 2 (HER2) testing to select patients for targeted therapy has been proposed. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA or circulating tumor cell testing (also known as a liquid biopsy) is proposed as a non-invasive alternative.

Summary of Evidence

For individuals with metastatic CRC who receive KRAS, NRAS, BRAF, NTRK,or HER2 testing to guide treatment, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and National Comprehensive Cancer Network (NCCN) recommendations.

For individuals with metastatic CRC who receive circulating tumor DNA or circulating tumor cell testing (liquid biopsy) to guide treatment, the evidence includes observational studies. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, and medication use. Given the breadth of methodologies available to assess circulating tumor DNA and circulating tumor cells, the clinical validity of each commercially available test must be established independently. The clinical validity of the OncoBEAM™ RAS CRC Assay has been studied in multiple observational studies. When compared to tissue biopsy, sensitivity ranged from 70% (51% to 84%) to 96% (95% CI, 87% to 100%) and specificity ranged from 83% (95% CI, 71% to 92%) to 94% (82% to 98%). FoundationOne® Liquid has been compared to tissue biopsy with the FoundationACT™ assay in 1 observational study; positive percent agreement was 80% overall and 90% when tissue and liquid biopsy were collected less than 270 days apart. Clinical validity studies were limited by unclear reporting of blinding, use of convenience rather than consecutive samples, and variation in the timing of sample collection. There are no published studies reporting clinical outcomes or clinical utility. 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 review is to summarize the evidence and guidelines on using biomarker testing to select treatment with U.S. Food and Drug Administration (FDA)-approved targeted therapy for individuals with metastatic colorectal cancer (CRC).

Policy STATEMENT

KRAS, NRAS, BRAF, NTRK, or HER2 testing of tumor tissue may be considered medically necessary for individuals with metastatic colorectal cancer to select individuals for treatment with U.S. Food and Drug Administration (FDA)-approved therapies.

All other uses of KRAS, NRAS, BRAF, NTRK, or HER2 testing of tumor tissue to guide colorectal cancer targeted therapy are considered investigational.

Circulating tumor DNA testing (liquid biopsy) to guide treatment in individuals with metastatic colorectal cancer is considered investigational. (see Policy Guidelines)

Policy Guidelines

The National Comprehensive Cancer Network (NCCN) colon cancer guidelines v. 3.202 4 and rectal cancer guidelines v. 3.202 4 do not recommend testing for specific genes over a next generation sequencing panel. The guidelines additionally state that testing may be performed using either tissue or blood-based biopsy, with testing on tissue being preferred.

For expanded panel testing, see evidence review 2.04.115.

Testing for other variants may become available between policy updates.

Testing for individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics 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.

For somatic biomarker testing related to use of immune checkpoint inhibitor therapy (BRAF, microsatellite instability/mismatch repair [MSI/MMR], PD-L1, tumor mutational burden [TMB]), see evidence review 2.04.157.

Note that TMB is often included in panel tests, and might not have separate coding; Plans with coverage for panels might consider local decision for TMB.

FDA approves tests in between policy review cycles. As such, newly approved tests might need to be considered per local Plan discretion. 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.

Note: Extensive evidence review is not included for somatic tests of individual genes (not gene panels) associated with FDA -approved therapies with National Comprehensive Cancer Network (NCCN recommendations of 2A or higher. The pivotal evidence is included in Table 2 for informational purposes. Additionally, no evidence review is provided for somatic tests of individual genes that do not have associated FDA-approved therapies regardless of NCCN recommendations, as these off-label therapies are deemed investigational per the Blue Cross and Blue Shield Association Medical Policy Program Policies and Procedures.

Coding

Please 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

KRAS, NRAS, and BRAF Variants

Cetuximab (Erbitux^®; ImClone Systems) and panitumumab (Vectibix^®; Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization. The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. The RAS proteins are G proteins that cycle between active (RAS guanosine triphosphate) and inactive (RAS guanosine diphosphate) forms in response to stimulation from a cell surface receptor, such as EGFR, and they act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic variants that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. Approximately 40% of colorectal cancers (CRCs) have KRAS variants in codons 12 and 13 in exon 2. Another proto-oncogene that acts downstream from KRAS-NRAS harbors oncogenic variants in codons 12, 13, or 61 that result in constitutive activation of the EGFR-mediated pathway. These variants are less common compared with KRAS, detected in 2% to 7% of CRC specimens. It is unclear whether NRAS variants predict poor response due to anti-EGFR monoclonal antibody therapy or are prognostic of poor CRC outcomes in general. A third proto-oncogene, BRAF, encodes a protein kinase and is involved in intracellular signaling and cell growth; BRAF is also a principal downstream effector of KRAS. BRAF variants occur in fewer than 10% to 15% of CRCs and appear to be a marker of poor prognosis. KRAS and BRAF variants are considered to be mutually exclusive.

Cetuximab and panitumumab have marketing approval from the U.S. Food and Drug Administration (FDA) for the treatment of metastatic CRC in the refractory disease setting. The FDA approval for panitumumab indicates that panitumumab is not indicated for the treatment of patients with KRAS or NRAS variant-positive disease in combination with oxaliplatin-based chemotherapy.^1,

A large body of literature has shown that metastatic CRC tumors with a variant in exon 2 (codon 12 or 13) of the KRAS gene do not respond to cetuximab or panitumumab therapy. More recent evidence has shown that variants in KRAS outside exon 2 (ie, in exons 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) and variants in NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) also predict a lack of response to these monoclonal antibodies. Variant testing of these exons outside the KRAS exon 2 is referred to as extended RAS testing.

Human Epidermal Growth Factor Receptor 2 Amplification/Overexpression

Human epidermal growth factor receptor 2 (HER2) is a member of the HER (EGFR) family of tyrosine kinase receptors and has no specific ligand. When activated, it forms dimers with other EGFR family members. Amplification of HER2 is detected in approximately 3% of patients with CRC, with higher prevalence in RAS/BRAF-wild type tumors (5% to 14%). In addition to its role as a predictive marker for HER2-targeted therapy, HER2 amplification/overexpression is being investigated as a predictor of resistance to EGFR-targeting monoclonal antibodies.
 

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing

The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry.^2, Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusion transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners.

Detecting Circulating Tumor DNA and Circulating Tumor Cells (Liquid Biopsy)

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.

Typically, the evaluation of RAS mutation status requires tissue biopsy. Circulating tumor DNA (ctDNA) testing is proposed as a non-invasive alternative.

Detection of ctDNA is challenging because ctDNA is diluted by nonmalignant circulating DNA and usually represents a small fraction (<1%) of total ctDNA. Therefore, more sensitive methods than the standard sequencing approaches (eg, Sanger sequencing) are needed.

Highly sensitive and specific methods have been developed to detect ctDNA, for both single nucleotide variants (eg, BEAMing [which combines emulsion polymerase chain reaction with magnetic beads and flow cytometry] and digital polymerase chain reaction) and copy-number variants. Digital genomic technologies allow for enumeration of rare variants in complex mixtures of DNA.

Approaches to detecting ctDNA can be considered targeted, which includes the analysis of known genetic mutations from the primary tumor in a small set of frequently occurring driver mutations, or untargeted without knowledge of specific variants present in the primary tumor, which includes array comparative genomic hybridization, next-generation sequencing, and whole exome and genome sequencing. Targeted testing may impact therapy selection.

Circulating tumor cell assays usually start with an enrichment step that increases the concentration of circulating tumor cells, either by biologic properties (expression of protein markers) or physical properties (size, density, electric charge). Circulating tumor cells can then be detected using immunologic, molecular, or functional assays.

A number of liquid biopsy tests related to targeted treatment of metastatic CRC have been developed (Table 1).

Table 1. Examples of Liquid Biopsy Tests Related to Targeted Treatment of Metastatic Colorectal Cancer

CTC: circulating tumor cell; ctDNA: circulating tumor DNA.

Regulatory Status

Table 2 summarizes the targeted treatments approved by the FDA for patients with CRC, along with the approved companion diagnostic tests. The information in Table 2 was current as of May 24, 2024; FDA maintains a list of cleared or approved companion diagnostic devices that is updated regularly.^3,

In June 2022, FDA granted accelerated approval to to dabrafenib (Tafinlar®, Novartis) in combination with trametinib (Mekinist®, Novartis) for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutations who have progressed following prior treatment and have no satisfactory alternative treatment options. However, dabrafenib in combination with trametinib is not indicated for patients with CRC because of known intrinsic resistance to BRAFinhibition.^4, Therefore, BRAF V600E variant testing to select individuals for treatment with dabrafenib in combination with trametinib is not included in this evidence review and is not listed in Table 2.

Table 2. Targeted Treatments for Metastatic Colorectal Cancer and U.S. Food and Drug Administration-Approved Companion Diagnostic Tests

Source: FDA (2024)^3,
CRC: colorectal cancer; EGFR: epidermal growth factor receptor; FDA: U.S. Food and Drug Administration; FOLFIRI: leucovorin, fluorouracil and irinotecan; FOLFOX: leucovorin, fluorouracil, and oxaliplatin; HER2: human epidermal growth factor receptor 2; mCRC: metastatic CRC; NCCN: National Comprehensive Cancer Network

Laboratory-Developed Tests

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 under CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

Rationale

This evidence review was created in October 2008 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 24, 2024.

Testing for individual genes (not gene panels) associated with U.S. Food and Drug Administration (FDA)-approved therapeutics (ie, as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence review. The pivotal evidence is included in Table 1 for informational purposes. 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.

Population Reference No. 1

KRAS, NRAS, BRAF, NTRK, and HER2 Variant Testing to Guide Treatment for Metastatic Colorectal Cancer

For individuals with metastatic colorectal cancer ( CRC) who receive KRAS, NRAS, BRAF, NTRK, or HER2 gene variant testing to select treatment with FDA-approved targeted therapy, the evidence includes FDA-approved therapeutics with NCCN recommendations of 2A or higher and was not extensively evaluated.

For individuals with metastatic CRC who receive KRAS, NRAS, BRAF, NTRK,or HER2 testing to guide treatment, the evidence includes FDA-approved therapeutics with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher and was not extensively evaluated. The evidence includes the pivotal studies leading to the FDA and National Comprehensive Cancer Network (NCCN) recommendations.

Population Reference No. 2

Circulating Tumor DNA Testing (Liquid Biopsy) to Guide Treatment for Metastatic Colorectal Cancer

Clinical Context and Test Purpose

One purpose of liquid biopsy testing of individuals who have metastatic CRC is to inform a decision regarding treatment selection (eg, whether to select a targeted treatment or standard treatment).

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

Populations

The relevant population of interest is individuals with metastatic CRC being considered for targeted therapy.

Interventions

The test being considered is liquid biopsy using either circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). Both targeted polymerase chain reaction-based assays and broad next-generation sequencing-based approaches are available.

Comparators

In patients who are able to undergo a biopsy, molecular characterization of the tumor is performed using standard tissue biopsy samples. Patients unable to undergo a biopsy generally receive standard therapy.

Outcomes

True-positive liquid biopsy test results lead to the initiation of appropriate treatment (eg, targeted therapy) without a tissue biopsy. False-positive liquid biopsy test results lead to the initiation of inappropriate therapy, which could shorten progression-free survival (PFS).

In individuals able to undergo a tissue biopsy, negative liquid biopsies reflex to tissue testing. In individuals unable to undergo a tissue biopsy, a negative liquid biopsy result would not change empirical treatment. Therefore, health outcomes related to negative test results do not differ between liquid biopsy and tissue biopsy.

The time frame for outcomes measures varies from several months to several years.

Study Selection Criteria

For the evaluation of clinical validity, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Given the breadth of molecular diagnostic methodologies available to assess ctDNA and CTC, the clinical validity of each commercially available test must be established independently. Multiple high-quality studies are needed to establish the clinical validity of a test.

OncoBEAM RAS CRC Assay

The clinical validity of the OncoBEAM RAS CRC assay has been evaluated in several published studies of patients with metastatic CRC. Study characteristics and results are shown in Tables 3 and 4. Study relevance, design, and conduct limitations are described in Tables and 8.

Table 3. Clinical Validity Studies of the OncoBEAM RAS Assay

CRC: colorectal cancer; EGFR: epidermal growth factor receptor; FOLFIRI: folinic acid, fluorouracil, irinotecan; NGS: next-generation sequencing; PCR: polymerase chain reaction.

Table 4. Clinical Validity Studies of the OncoBEAM RAS Assay-Results

 NA: not available; NPV: negative predictive value; NR: not reported; PPV: positive predictive value.
^a With tissue biopsy reference standard.
^b Values are percent with 95% confidence interval.
^b Confidence intervals not reported in publication; calculated from data provided.

FoundationACT ctDNA Assay

The FoundationACT ctDNA assay, the predecessor of FoundationOne Liquid, was compared to tissue biopsy using the FoundationOne assay in one manufacturer-sponsored study by Li et al in 2019.^18, Study characteristics and results are shown in Tables 5 and 6. The researchers reported results on the subset of 51 patients with KRAS, NRAS, and BRAF variants. These results are shown in Table 10. Positive percent agreement was 80% for all time points for short variants and increased to 90% for cases in which tissue and liquid biopsy were measured less than 270 days apart. Limitations of this study are described in Tables 7 and 8.

Table 5. Clinical Validity Study of the FoundationACT ctDNA Assay

CRC: colorectal cancer; ctDNA: circulating tumor DNA.

Table 6. Clinical Validity Study of the FoundationACT ctDNA Assay - Results

ctDNA: circulating tumor DNA ;.

Table 7. Study Relevance Limitations for Clinical Validity Studies of Liquid Biopsy in Metastatic Colorectal Cancer

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
NPV: negative predictive value; PPV: positive predictive value.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 8. Study Design and Conduct Limitations for Liquid Biopsy in Metastatic Colorectal Cancer

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
CI: confidence interval; ctDNA: circulating tumor DNA.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Follow-Up key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples/patients excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified on the clinical utility of liquid biopsy to guide treatment for patients with metastatic CRC.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Circulating Tumor DNA Testing (Liquid Biopsy) to Guide Treatment for Metastatic Colorectal Cancer

The clinical validity of the OncoBEAM RAS CRC Assay has been studied in multiple observational studies. When compared to tissue biopsy, sensitivity ranged from 70% (95% confidence interval [CI], 51% to 84%) to 96% (95% CI, 87% to 100%) and specificity ranged from 83% (95% CI, 71% to 92%) to 94% (95% CI, 82% to 98%). FoundationOne Liquid has been compared to tissue biopsy with the FoundationACT assay in 1 observational study; positive percent agreement was 80% overall and 90% when tissue and liquid biopsy were collected less than 270 days apart. Clinical validity studies were limited by unclear reporting of blinding, use of convenience rather than consecutive samples, and variation in the timing of sample collection. There are no published studies reporting clinical outcomes or clinical utility.

For individuals with metastatic CRC who receive circulating tumor DNA or circulating tumor cell testing (liquid biopsy) to guide treatment, the evidence includes observational studies. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, and medication use. Given the breadth of methodologies available to assess circulating tumor DNA and circulating tumor cells, the clinical validity of each commercially available test must be established independently. The clinical validity of the OncoBEAM™ RAS CRC Assay has been studied in multiple observational studies. When compared to tissue biopsy, sensitivity ranged from 70% (51% to 84%) to 96% (95% CI, 87% to 100%) and specificity ranged from 83% (95% CI, 71% to 92%) to 94% (82% to 98%). FoundationOne® Liquid has been compared to tissue biopsy with the FoundationACT™ assay in 1 observational study; positive percent agreement was 80% overall and 90% when tissue and liquid biopsy were collected less than 270 days apart. Clinical validity studies were limited by unclear reporting of blinding, use of convenience rather than consecutive samples, and variation in the timing of sample collection. There are no published studies reporting clinical outcomes or clinical utility. 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 reference medical policy 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 et al

In 2017, the American Society of Clinical Oncology along with American Society for Clinical Pathology, College of American Pathologists, and Association for Molecular Pathology published guidelines on molecular biomarkers for the evaluation of colorectal cancer.^19, Table 9 summarizes the relevant guidelines.

Table 9. Summary of Recommendations

EGFR: epidermal growth factor receptor; MLH1: mutL homolog 1;MMR: mismatch repair; QOE: quality of evidence; SOE: strength of evidence.

National Comprehensive Cancer Network

The following information is based on the National Comprehensive Cancer Network (NCCN) guidelines on the treatment of colon cancer (v. 3.2024 ).^7, Guidelines are updated frequently; refer to the source document for most recent updates and for additional detail.

RAS and BRAF Testing

The guidelines recommend that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRASand NRAS) and BRAF variants, individually or as part of a next-generation sequencing panel, for all patients with metastatic colon cancer Patients with any known KRASmutation (exon 2, 3, 4) or NRASmutation (exon 2, 3, 4) should not be treated with either cetuximab or panitumumab. BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor (Category 2A).

NTRK

The guidelines acknowledge that NTRK fusions are extremely rare in colorectal cancer, and typically limited to tumors that are wild-type for KRAS, NRAS, and BRAF. NTRK inhibitors have been shown to have activity only in those cases with NTRK fusions, and not with NTRK point mutations. Selection of the appropriate assay for NTRK fusion detection is stated to depend on "tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently."

Human Epidermal Receptor 2 Testing

The guidelines recommend testing for human epidermal receptor 2 (HER2) amplifications for patients with metastatic colorectal cancer. Anti-HER2 therapy is only indicated in HER2-ampliified tumors that are also RAS and BRAFwild type. If the tumor is already known to have a KRAS/NRAS or BRAF mutation, HER2 testing is not indicated.(Category 2A) HER2 testing is performed via immunohistochemistry (IHC) with some results requiring reflex to fluorescence in situ hybridization (FISH); and, next-generation sequencing (NGS) is another methodology endorsed for testing for HER2 amplification.

Circulating Tumor DNA

The NCCN colon cancer guidelines state that determination of gene status for KRAS/NRAS and BRAF mutations may be carried out using either a tissue or blood-based (eg, liquid) biopsy, although tissue based testing is preferred.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

A March 2018 decision memo from the Centers for Medicare & Medicaid Services addressed next-generation sequencing for Medicare beneficiaries with advanced cancer.^20, The memo states:

The Centers for Medicare & Medicaid Services has determined that NGS as a diagnostic laboratory test is reasonable and necessary and covered nationally when performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:

1. Patient has:

1. 1. 1. either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and

      2. either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and

      3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

2. The diagnostic laboratory test using NGS must have:

1. 1. FDA [U.S. Food and Drug Administration] approval or clearance as a companion in vitro diagnostic; and

   2. an FDA [U.S. Food and Drug Administration] approved or cleared indication for use in that patient's cancer; and

   3. results provided to the treating physician for management of the patient using a report template to specify treatment options.

Regarding liquid biopsies, the memo states, "The NCD does not limit coverage to how to prepare a sample for performing a diagnostic laboratory test using NGS. Commenters submitted published articles on liquid biopsies (also referred to as circulating tumor DNA (ctDNA) or plasma cell-free DNA (cfDNA) tests). We reviewed and included in the evidence and analysis of 4 studies on liquid biopsies. At this time, liquid-based multi-gene sequencing panel tests are left to contractor discretion if certain patient criteria are met."^20,

Ongoing and Unpublished Clinical Trials

Currently unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Ongoing Trials

NCT: national clinical trial.

References

1. Amgen Inc. Vectibix (panitumumab) prescribing information. 2015; https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125147s200lbl.pdf. Accessed May 24, 2024.
2. TRK Fusion Cancer (Testing). https://trkcancer.com/testing. Accessed May 19, 2024.
3. U.S. Food & Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools. Accessed May 30, 2024.
4. Food & Drug Administration. 2022. FDA Grants Accelerated Approval to Dabrafenib in Combination with Trametinib for Unresectable or Metastatic Solid Tumors with BRAF V600E Mutation. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid. Accessed May 24, 2024.
5. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. Apr 02 2009; 360(14): 1408-17. PMID 19339720
6. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. Feb 05 2009; 360(6): 563-72. PMID 19196673
7. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed May 30, 2024.
8. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. Oct 24 2019; 381(17): 1632-1643. PMID 31566309
9. Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer. Clin Cancer Res. Dec 15 2015; 21(24): 5469-79. PMID 26341920
10. Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. May 2023; 24(5): 496-508. PMID 37142372
11. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. Feb 22 2018; 378(8): 731-739. PMID 29466156
12. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. Feb 2020; 21(2): 271-282. PMID 31838007
13. García-Foncillas J, Tabernero J, Élez E, et al. Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer. Br J Cancer. Dec 2018; 119(12): 1464-1470. PMID 30467411
14. Vidal J, Muinelo L, Dalmases A, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol. Jun 01 2017; 28(6): 1325-1332. PMID 28419195
15. Schmiegel W, Scott RJ, Dooley S, et al. Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: concordance of results from circulating tumor DNA and tissue-based RAS testing. Mol Oncol. Feb 2017; 11(2): 208-219. PMID 28106345
16. Grasselli J, Elez E, Caratù G, et al. Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol. Jun 01 2017; 28(6): 1294-1301. PMID 28368441
17. Normanno N, Esposito Abate R, Lambiase M, et al. RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial. Ann Oncol. Jan 01 2018; 29(1): 112-118. PMID 28950295
18. Li G, Pavlick D, Chung JH, et al. Genomic profiling of cell-free circulating tumor DNA in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy. J Gastrointest Oncol 2019. http://jgo.amegroups.com/article/view/29063. Accessed May 24, 2024.
19. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn. Mar 2017; 19(2): 187-225. PMID 28185757
20. Centers for Medicare & Medicaid Services. Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450N). March 16, 2018. https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=290. Accessed May 30, 2024.

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