Medical Policy

Policy Num:      11.003.026
Policy Name:    Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
Policy ID:          [11.003.026]  [Ac / B / M- / P-]  [2.04.115]

Last Review:      March 20, 2025
Next Review:     November 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
11.003.064 - Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

Summary

Description

Comprehensive genomic profiling offers the potential to evaluate a large number of genetic markers at a single time to identify cancer treatments that target specific biologic pathways. Some individual markers have established benefit in certain types of cancers; they are not addressed in this evidence review. Rather, this review focuses on "expanded" panels, which are defined as molecular panels that test a wide variety of genetic markers in cancers without regard for whether a specific targeted treatment has demonstrated benefit. This approach may result in treatment different from that usually selected for a patient based on the type and stage of cancer.

Summary of Evidence

For individuals who have advanced cancer that is being considered for targeted therapy who receive comprehensive genomic profiling of tumor tissue, the evidence includes a randomized controlled trial, nonrandomized trials, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-specific survival, test validity, and quality of life. A large number of variants and many types of cancer preclude determination of the clinical validity of the panels as a whole, and clinical utility has not been demonstrated for the use of expanded molecular panels to direct targeted cancer treatment. The 1 published randomized controlled trial (SHIVA trial) that used an expanded panel reported no difference in progression-free survival compared with standard treatment. Additional randomized and nonrandomized trials for drug development, along with systematic reviews of these trials, have compared outcomes in patients who received molecularly targeted treatment with patients who did not. Generally, trials in which therapy was targeted to a gene variant resulted in improved response rates, progression-free survival, and overall survival compared to patients in trials who did not receive targeted therapy. A major limitation in the relevance of these studies for comprehensive genomic profiling is that treatment in these trials was guided both by the tissue source and the molecular target for drug development, rather than being matched solely by the molecular marker (ie, basket trials). As a result, these types of studies do not provide evidence of the benefit of broad molecular profiling compared to more limited genetic assessments based on known tumor-specific variants. Basket trials that randomize patients with various tumor types to a strategy of comprehensive genomic profiling followed by targeted treatment are needed, and several are ongoing. 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 comprehensive genomic profiling improves the net health outcome of individuals with advanced cancer.

POLICY Statement

The use of comprehensive genomic profiling for selecting targeted cancer treatment is considered investigational.

POLICY GUIDELINES

Coding

See coding table

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

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

Traditional Therapeutic Approaches to Cancer

Tumor location, grade, stage, and the patient's underlying physical condition have traditionally been used in clinical oncology to determine the therapeutic approach to specific cancer, which could include surgical resection, ionizing radiation, systemic chemotherapy, or combinations thereof. Currently, some 100 different types are broadly categorized according to the tissue, organ, or body compartment in which they arise. Most treatment approaches in clinical care were developed and evaluated in studies that recruited subjects and categorized results based on this traditional classification scheme.

This traditional approach to cancer treatment does not reflect the wide diversity of cancer at the molecular level. While treatment by organ type, stage, and grade may demonstrate statistically significant therapeutic efficacy overall, only a subgroup of patients may derive clinically significant benefits. It is unusual for cancer treatment to be effective for all patients treated in a traditional clinical trial. Spear et al (2001) analyzed the efficacy of major drugs used to treat several important diseases.^1, They reported heterogeneity of therapeutic responses, noting a low rate of 25% for cancer chemotherapeutics, with response rates for most drugs falling in the range of 50% to 75%. The low rate for cancer treatments is indicative of the need for better identification of characteristics associated with treatment response and better targeting of treatment to have higher rates of therapeutic responses.

Targeted Cancer Therapy

Much of the variability in clinical response may result from genetic variations. Within each broad type of cancer, there may be a large amount of variability in the genetic underpinnings of cancer. Targeted cancer treatment refers to the identification of genetic abnormalities present in the cancer of a particular patient, and the use of drugs that target the specific genetic abnormality. The use of genetic markers allows cancers to be further classified by "pathways" defined at the molecular level. An expanding number of genetic markers have been identified. These may be categorized into 3 classes:^2, (1) genetic markers that have a direct impact on care for the specific cancer of interest, (2) genetic markers that may be biologically important but are not currently actionable, and (3) genetic markers of uncertain importance.

A smaller number of individual genetic markers fall into the first category (ie, have established utility for a particular cancer type). The utility of these markers has been demonstrated by randomized controlled trials that select patients with the marker and report significant improvements in outcomes with targeted therapy compared with standard therapy. Testing for individual variants with established utility is not covered in this evidence review. In some cases, limited panels may be offered that are specific to 1 type of cancer (eg, a panel of several markers for non-small-cell lung cancer). This review also does not address the use of cancer-specific panels that include a few variants. Rather, this review addresses expanded panels that test for many potential variants that do not have established efficacy for the specific cancer in question.

When advanced cancers are tested with expanded molecular panels, most patients are found to have at least 1 potentially pathogenic variant.^3,4,5, The number of variants varies widely by types of cancers, different variants included in testing, and different testing methods among the available studies. In a study by Schwaederle et al (2015), 439 patients with diverse cancers were tested with a 236-gene panel.^5, A total of 1813 molecular alterations were identified, and almost all patients (420/439 [96%]) had at least 1 molecular alteration. The median number of alterations per patient was 3, and 85% (372/439) of patients had 2 or more alterations. The most common alterations were in the TP53 (44%), KRAS (16%), and PIK3CA (12%) genes.

Some evidence is available on the generalizability of targeted treatment based on a specific variant among cancers that originate from different organs.^2,6, There are several examples of variant-directed treatment that is effective in 1 type of cancer but ineffective in another. For example, targeted therapy for epidermal growth factor receptor variants have been successful in non-small-cell lung cancer but not in trials of other cancer types. Treatment with tyrosine kinase inhibitors based on variant testing has been effective for renal cell carcinoma but has not demonstrated effectiveness for other cancer types tested. "Basket" studies, in which tumors of various histologic types that share a common genetic variant are treated with a targeted agent, also have been performed. One such study was published by Hyman et al (2015).^7, In this study, 122 patients with BRAF V600 variants in nonmelanoma cancers were treated with vemurafenib. The authors reported that there appeared to be an antitumor activity for some but not all cancers, with the most promising results seen for non-small-cell lung cancer, Erdheim-Chester disease, and Langerhans cell histiocytosis.

Expanded Cancer Molecular Panels

Table 1 provides a select list of commercially available expanded cancer molecular panels.

Table 1. Commercially Available Molecular Panels for Solid and Hematologic Tumor Testing

    NGS: next-generation sequencing; PCR: polymerase chain reaction; WES: whole exome sequencing.

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. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.

FoundationOne CDx (Foundation Medicine) initially received premarket approval by the U.S. Food and Drug Administration (FDA) (P170019) in 2017. It is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies listed in Table 2. The approval is both tumor type and biomarker specific, and does not extend to all of the components included in the FoundationOne CDx product. The test is intended to identify patients who may benefit from treatment with targeted therapies in accordance with approved therapeutic product labeling. "Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms." FDA product code: PQP

In 2017, the Oncomine DX Target Test (Life Technologies Corp) received premarket approval by the FDA (P160045) to aid in selecting non-small cell lung cancer patients for treatment with approved targeted therapies. FDA product code: PQP

MSK-IMPACT (Memorial Sloan Kettering) received de novo marketing clearance in 2017 (DEN170058). "The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product." FDA product code: PZM

Subsequent marketing clearance through the FDA's 510(k) process (FDA product code PZM) include the following:

• Omics Core (NantHealth) received marketing clearance in 2019 (K190661). The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and tumor mutational burden.

• PGDx elio tissue complete (Personal Genome Diagnostics) received marketing clearance in 2020 (K192063). PGDx elio tissue complete is "intended to provide tumor mutation profiling information on somatic alterations (SNVs [single nucleotide variants], small insertions and deletions, one amplification and 4 translocations), microsatellite instability and tumor mutation burden (TMB)".

• The NYU Langone Genome PACT assay (NYU Langone Medical Center) is a 607-gene panel that received marketing clearance by the FDA in 2021 (K202304). The test assesses somatic point mutations, insertions and deletions smaller than 35 base pairs.

• ACTOnco (ACT Genomics) received marketing clearance in 2022 (K210017). The next-generation sequencing test is intended to provide information on point mutations, small insertions and deletions, ERBB2 gene amplification, and tumor mutational burden in patients with solid malignant neoplasms.
• xT CDx (Tempus Labs, Inc) is a 648-gene panel that received marketing clearance by the FDA in 2023. The test assesses single nucleotide variants and multi-nucleotide variants as well as insertion and deletion alterations in the included genes as well as microsatelite instability.

The intended use is by qualified health care professionals in accordance with professional guidelines for oncology, and not prescriptive for use of any specific therapeutic product.

OmniSeq Comprehensive® is approved by the New York State Clinical Laboratory Evaluation Program.

Table 2. Companion Diagnostic Indications for F1CDx¹

    F1CDx: FoundationOne Companion Diagnostic. 1 An updated list of FDA-cleared or -approved companion diagnostic devices is available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.

RATIONALE

This evidence review was developed in March 2014 and has been updated regularly with a literature review of the PubMed database. The most recent literature update was performed through August 13, 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

Comprehensive Genomic Profiling of Tumor Tissue

Clinical Context and Test Purpose

The purpose of comprehensive genomic profiling in individuals with cancer is to identify somatic variants in tumor tissue to guide treatment decisions with targeted therapies.

The question addressed in this evidence review is: In individuals with cancer that is being considered for targeted therapy, does the use of comprehensive genomic profiling of tumor tissue improve the net health outcome?

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

Populations

The relevant population of interest is individuals with advanced cancer who have not previously been treated with targeted therapy.

Interventions

The relevant intervention of interest is comprehensive genomic profiling of tumor tissue, including all major types of molecular variants, single nucleotide variants, small and large insertions, and deletions, copy number variants, and fusions in cancer-associated genes by next-generation sequencing technologies. Some tests may also evaluate microsatellite instability and tumor mutation burden.

Comparators

The following practice is currently being used to identify somatic variants in tumor tissue to guide treatment decisions: therapy guided by single-gene testing.

Outcomes

Beneficial outcomes are an increase in progression-free survival (PFS) and overall survival (OS). A beneficial outcome may also be the avoidance of ineffective therapy and its associated harms.

Harmful outcomes could occur if ineffective therapy is given based on test results, because there may be adverse events of therapy in the absence of a benefit.

A follow-up to monitor for outcomes varies from several months to several years, depending on the type and stage of cancer.

Study Selection Criteria

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).

The evidence on the clinical validity of expanded panels and comprehensive genomic profiling is incomplete. Because of a large number of variants contained in expanded panels, it is not possible to determine the clinical validity of the panels as a whole. While some variants have a strong association with one or a small number of specific malignancies, none has demonstrated high clinical validity across a wide variety of cancers. Some have reported that, after filtering variants by comparison with matched normal tissue and cancer variants databases, most identified variants are found to be false-positives.

The clinical validity of the panels as a whole cannot be determined because of the different variants and a large number of potential cancers for which they can be used. Clinical validity would need to be reported for each variant for a particular type of cancer. Because there are hundreds of variants included in the panels and dozens of cancer types, evaluation of the individual clinical validity for each pairing is beyond the scope of this review.

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.

The most direct way to demonstrate clinical utility is through controlled trials that compare a strategy of cancer variant testing followed by targeted treatment with a standard treatment strategy without variant testing. Randomized controlled trials (RCTs) are necessary to control for selection bias in treatment decisions, because clinicians may select candidates for variant testing based on clinical, demographic, and other factors. Outcomes of these trials would be the morbidity and mortality associated with cancer and cancer treatment. OS is most important; cancer-related survival and/or PFS may be acceptable surrogates. A quality-of-life measurement may also be important if study designs allow for treatments with different toxicities in the experimental and control groups.

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.

Review of Evidence

Randomized Controlled Trials

Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA trial) was an RCT of treatment directed by cancer variant testing versus standard care, with the first results published in 2015 (see Tables 3, 4, and 5).^8,9, Based on the pattern of abnormalities found, 9 different regimens of established cancer treatments were assigned to the experimental treatment arm. The primary outcome was PFS analyzed by intention to treat. Baseline clinical characteristics and tumor types were similar between groups.

Table 3. Summary of Key RCT Characteristics

    NGS: next-generation sequencing; RCT: randomized controlled trial. a Molecular alterations affecting the hormonal pathway were found in 82 (42%) patients; alterations affecting the PI3K/AKT/mTOR pathway were found in 89 (46%) patients; alterations affecting the RAF/MED pathway were found in 24 (12%) patients. b Variant testing included comprehensive analysis of 3 molecular pathways (hormone receptor pathway, PI3K/AKT/mTOR pathway, RAF/MEK pathway) performed by targeted next-generation sequencing, analysis of copy number variations, and hormone expression by immunohistochemistry.

Table 4. Treatment Algorithm for Experimental Arm From the SHIVA Trial

    Adapted from Le Tourneau et al (2012).8,

After a median follow-up of 11.3 months, the median PFS was 2.3 months in the targeted treatment group versus 2.0 months in the standard of care group (p=.41; see Table 5). In the subgroup analysis by molecular pathway, there were no significant differences in PFS between groups.

Table 5. Summary of Key RCT Results

    CI: confidence interval; HR: hazard ratio; PFS: progression-free survival; RCT: randomized controlled trial

Limitations of the SHIVA trial are shown in Tables 6 and 7. A major limitation of the SHIVA trial is that the population consisted of patients who had failed a targeted treatment.

Table 6. Study Relevance Limitations

    The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 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. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 7. Study Design and Conduct Limitations

    The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

A crossover analysis of the SHIVA trial by Belin et al (2017) evaluated the PFS ratio from patients who failed standard of care therapy and crossed over from molecularly targeted agent (MTA) therapy to treatment at physician's choice (TPC) or vice versa.^10, The PFS ratio was defined as the PFS on MTA to PFS on TPC in patients who crossed over. Of the 95 patients who crossed over, 70 patients crossed over from the TPC to MTA arm while 25 patients crossed over from MTA to TPC arm. In the TPC to MTA crossover arm, 26 (37%) of patients and 15 (61%) of patients in the MTA to TPC arm had a PFS on MTA to PFS on TPC ratio greater than 1.3. The post hoc analysis of the SHIVA trial has limitations because it only evaluated a subset of patients from the original clinical trial but used each patient as his/her control by using the PFS ratio. The analysis suggests that patients might have benefited from the treatment algorithm evaluated in the SHIVA trial.

Systematic Reviews

Systematic reviews compare the outcomes of patients who were enrolled in trials with personalized therapy with those of patients enrolled in non-personalized therapy trials (see Table 8). Schwaederle et al (2015) assessed outcomes in single-agent phase 2 trials, while Jardim et al (2015) evaluated trials for 58 newly approved cancer agents.^11,12, The results of the meta-analyses are shown in Table 9. Treatment directed by a personalized strategy was associated with an increased response rate, PFS, and OS compared to treatment that was not personalized. While these studies support a strategy of targeted therapy within a specific tumor type, they do not provide evidence that broad genomic profiling is more effective than tumor-specific variant assessment.

Table 8. Meta-Analysis Characteristics

    RCT: randomized controlled trial.

Table 9. Meta-Analysis Results

    CI: confidence interval; IQR: interquartile range; NS: reported as not significant. a This may be a typographical error in the publication.

Nonrandomized Controlled Trials

Nonrandomized studies have been published that use some type of control. These studies are summarized in a review by Zimmer et al (2019).^13, Some of these studies had a prospective, interventional design.^14, Another type of study compares patients matched to targeted treatment with patients not matched. In this type of study, all patients undergo comprehensive genetic testing, but only a subset is matched to targeted therapy. Patients who are not matched continue to receive standard care. These studies have reported that outcomes are superior in patients receiving matched treatment. However, there are potential issues with this design that could compromise the validity of comparing these 2 populations. They include the following: (1) differences in clinical and demographic factors, (2) differences in the severity of disease or prognosis of disease (ie, patients with more undifferentiated anaplastic cancers might be less likely to express genetic markers), and (3) differences in the treatments received. It is possible that one of the "targeted" drugs could be more effective than standard treatment whether or not patients were matched.

One of the largest studies of molecular targeting in phase 1 trials was the Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT) study, reported by Tsimberidou et al (2017) from the MD Anderson Cancer Center.^15, Patients with advanced cancer who underwent comprehensive genomic profiling were treated with matched targeted therapy when available (see Table 10). Out of 1436 patients who underwent genomic profiling, 1170 (82.1%) had 1 or more variants , of which 637 were actionable. The most frequent alterations were estrogen receptor overexpression, and variants in TP53, KRAS, PTEN, PIK3CA, and BRAF. Comparison of outcomes in patients who received matched and unmatched therapies are shown in Table 11. The group that had matched therapy had a higher response rate (11% vs. 5%), longer PFS (3.4 vs. 2.9 months), and longer OS (8.4 vs. 7.3 months). In addition to the general limitations of this type of study design, limitations in relevance and design and conduct are shown in Tables 12 and 13. Note that a randomized trial from this center that will compare matched to unmatched therapy (IMPACT 2) is ongoing with completion expected in 2024 (see Table 14).

Table 10. Summary of Key Nonrandomized Trial Study Characteristics

Table 11. Summary of Key Nonrandomized Trial Study Results

    CI: confidence interval; HR: hazard ratio;;.

Table 12. Study Relevance Limitations

    The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 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. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 13. Study Design and Conduct Limitations

    The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias. b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials). e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference. f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Non-Comparative Studies

NCI-MATCH is a master basket trial protocol in which tumors of various types are sequenced and patients assigned to targeted treatment based on the molecular alteration.^16, A total of 6391 patients were enrolled across 1117 clinical sites between 2015 and 2017 and underwent tumor sequencing. Patients had received a median of 3 lines of prior therapy. Common tumors comprised 37.5% of the total; the remainder had less common tumor histologies. Sequencing included 143 genes, of which approximately 40% of alterations were considered actionable, and 18% of patients were assigned to 30 treatment subprotocols. The majority of alterations identified in the 143 gene panel were either not actionable or led to experimental treatments in clinical trials. Response to treatments in the subprotocols are being reported and will provide preliminary evidence on tumor agnostic treatments.^17,18,19, Co-alterations discovered in NCI-MATCH have also led to a new biomarker-selected combination therapy trial by the National Cancer Institute, NCI-COMBOMATCH. Controlled basket trials that compare tumor-agnostic treatment based on a molecular marker with standard treatments are ongoing (see Table 14).

Section Summary: Clinically Useful

Evidence on targeted therapy for the treatment of various cancers includes an RCT, systematic reviews of phase 1, 2 and 3 trials, and a database review. The 1 published RCT (SHIVA trial) that used an expanded panel reported no difference in PFS compared with standard treatment. Additional randomized and nonrandomized trials for drug development, along with systematic reviews of these trials, have compared outcomes in patients who received molecularly targeted treatment with patients who did not. Generally, trials in which therapy was targeted to a gene variant resulted in improved response rates, PFS, and OS compared to patients in trials who did not receive targeted therapy. A major limitation in the relevance of these studies for comprehensive genomic profiling is that treatment in these trials was guided both by the tissue source and the molecular target for drug development, rather than being matched solely by the molecular marker (ie, basket trials). As a result, these types of studies do not provide evidence of the benefit of broad molecular profiling compared to limited genetic assessment based on known tumor-specific variants. Therefore, the clinical utility has not been demonstrated for the use of expanded molecular panels to direct targeted cancer treatment. RCTs that randomize patients with various tumor types to a strategy of comprehensive genomic profiling followed by targeted treatment are ongoing.

Summary of Evidence

For individuals who have advanced cancer that is being considered for targeted therapy who receive comprehensive genomic profiling of tumor tissue, the evidence includes an RCT , nonrandomized trials, and systematic reviews of these studies. Relevant outcomes are OS, disease-specific survival, test validity, and quality of life. A large number of variants and many types of cancer preclude determination of the clinical validity of the panels as a whole, and clinical utility has not been demonstrated for the use of expanded molecular panels to direct targeted cancer treatment. The 1 published randomized controlled trial (SHIVA trial) that used an expanded panel reported no difference in PFS compared with standard treatment. Additional randomized and nonrandomized trials for drug development, along with systematic reviews of these trials, have compared outcomes in patients who received molecularly targeted treatment with patients who did not. Generally, trials in which therapy was targeted to a gene variant resulted in improved response rates, PFS, and OS compared to patients in trials who did not receive targeted therapy. A major limitation in the relevance of these studies for comprehensive genomic profiling is that treatment in these trials was guided both by the tissue source and the molecular target for drug development, rather than being matched solely by the molecular marker (ie, basket trials). As a result, these types of studies do not provide evidence of the benefit of broad molecular profiling compared to more limited genetic assessments based on known tumor-specific variants. Basket trials that randomize patients with various tumor types to a strategy of comprehensive genomic profiling followed by targeted treatment are needed, and several are ongoing. 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

In 2022, the American Society of Clinical Oncology (ASCO) published a provisional clinical opinion based on informal consensus in the absence of a formal systematic review on the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors.^22, 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 status (dMMR) 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-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).

College of American Pathologists et al

In 2018, the College of American Pathologists, International Association for the Study of Lung Cancer, and the Association for Molecular Pathology updated their joint guidelines on molecular testing of patients with non-small-cell lung cancer.^23, The groups gave a strong recommendation for EGFR, ALK, and ROS1 testing. Based on expert consensus opinion KRAS was recommended as a single gene test if EGFR, ALK, and ROS1 were negative. Tests that were not recommended for single gene testing outside of a clinical trial were BRAF, RET, ERBB2 (HER2), and MET, although these genes should be tested if included in a panel.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines contain recommendations for specific genetic testing for individual cancers, based on situations where there is a known mutation-drug combination that has demonstrated benefits for that specific tumor type. Some examples of recommendations for testing of common solid tumors are listed below:

Breast cancer^24,

• HER2 testing for all new primary or newly metastatic breast cancers, BRCA1/2, ESR1, PIK3CA, NTRK fusions, RET fusions, microsatellite instability and mismatch repair, and tumor mutational burden.

Colon cancer^25,

• KRAS, NRAS, and BRAF mutation testing, HER2 amplification, NTRK fusions, RET fusions and microsatellite instability or mismatch repair testing for patients with metastatic colon cancer.

Non-small-cell lung cancer^26,

• EGFR, ALK, ROS1, BRAF, MET exon 14, RET, KRAS, HER2, and NTRK fusions.

Cutaneous melanoma^27,

• BRAF, NRAS, KIT.

• Uncommon mutations with next-generation sequencing are ALK, ROS1, NTRK, and BRAF fusions.

Ovarian cancer^28,

• BRCA 1/2, BRAF, NTRK, HER2, HRD, RET, FRα, tumor mutational burden, microsatellite instability and mismatch repair.

Pancreatic cancer^29,

• ALK, NRG1, NTRK, ROS1, FGRF2, RET, BRAF, BRCA1/2, HER2, KRAS, PALB2, mismatch repair deficiency, microsatellite instability, or tumor mutational burden.

Prostate cancer^30,

• BRCA1, BRCA2, ATM, ATR, PALB2, FANCA, MLH1, MRE11A, NBN, RAD51, CHEK2, CDK12, microsatellite instability, tumor mutational burden, and mismatch repair deficiency.

Updated recommendations for testing of solid tumors can be accessed at https://www.nccn.org/guidelines.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

The Centers for Medicare and Medicaid Services will cover diagnostic testing with next-generation sequencing for beneficiaries with recurrent, relapsed, refractory, metastatic cancer, or advanced stages III or IV cancer if the beneficiary has not been previously tested using the same next-generation sequencing test, unless a new primary cancer diagnosis is made by the treating physician, and if the patient has decided to seek further cancer treatment (CAG-00450N). The test must have a U.S. Food and Drug Administration approved or cleared indication as an in vitro diagnostic, with results and treatment options provided to the treating physician for patient management.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials+

    NCT: national clinical trial. a Industry-sponsored or co-sponsored.

References

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Codes

Policy History