Subject:
Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Genetic panel testing 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 specific targeted treatment has demonstrated benefit. This approach may result in a treatment different from that usually selected for a patient based on the type and stage of cancer.
Populations | Interventions | Comparators | Outcomes |
Individuals:
· With cancer that is being considered for targeted therapy | Interventions of interest are:
· Testing of tumor tissue with an expanded cancer molecular panel | Comparators of interest are:
· Single gene molecular testing | Relevant outcomes include:
· Overall survival
· Disease-specific survival
· Test validity
· Quality of life |
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 a 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 benefit. It is unusual for a 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 the 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. Dienstmann et al (2013) categorized these findings into 3 classes,2 which are listed following: (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 one 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.3-5 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 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
Test | Manufacturer | Tumor Type | Technology |
| FoundationOne® CDx test | Foundation Medicine | Solid | NGS |
| FoundationOne® CDx Heme test | Foundation Medicine | Hematologic | RNA sequencing |
| OnkoMatch™ | GenPath Diagnostics | Solid | Multiplex PCR |
| GeneTrails® Solid Tumor Panel | Knight Diagnostic Labs | Solid |  |
| Tumor profiling service | Caris Molecular Intelligence through Caris Life Sciences | Solid | Multiple technologies |
| SmartGenomics™ | PathGroup | Solid and hematologic | NGS, cytogenomic array, other technologies |
| Guardant360 panel {GuardantHealth, 2015 #399} | GuardantHealth | Solid | Digital sequencing |
| Paradigm Cancer Diagnostic (PcDx™) Panel | Paradigm | Solid | NGS |
| Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets | MSK-IMPACT™; Memorial Sloan Kettering Cancer Center | Solid | NGS |
| TruSeq® Amplicon Panel | | Solid | NGS |
| Illumina TruSight™ Tumor | Illumina | Solid | NGS |
| Ion AmpliSeq™ Comprehensive Cancer Panel | | Solid | NGS |
| Ion AmpliSeq™ Cancer Hotspot Panel v2 | Thermo Fisher Scientific | Solid | NGS |
| OmniSeq Comprehensive | OmniSeq | Solid | NGS |
NGS: next-generation sequencing; PCR: polymerase chain reaction.
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. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Related Policies
- Genetic Cancer Susceptibility Panels Using Next Generation Sequencing (Policy #084 in the Pathology Section)
Policy:
(NOTE: For services provided August 1, 2017 and after, Horizon Blue Cross Blue Shield of New Jersey collaborates with eviCore healthcare to conduct Medical Necessity Determination for certain molecular and genomic testing services for members enrolled in Horizon BCBSNJ fully insured products as well as Administrative Services Only (ASO) accounts that have elected to participate in the Molecular and Genomic Testing Program (“the Program”). Beginning August 1, 2017, the criteria and guidelines included in this policy apply to members enrolled in plans that have NOT elected to participate in the Program.
To access guidelines that apply for services provided August 1, 2017 and after to members enrolled in plans that HAVE elected to participate in the Program, please visit www.evicore.com/healthplan/Horizon_Lab.
Also note that this policy only addresses testing for acquired mutations from tumor tissue. This policy does not apply to tumor marker testing for hematologic malignancies, tumor markers addressed in a separate policy on ‘Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management [Liquid Biopsy], and testing for germline or inherited mutations in genes related to hereditary cancer syndromes.
For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)
1. Expanded tumor marker panels using next generation sequencing (e.g., FoundationOne CDx, Caris Tumor Profiling, Paradigm Cancer Diagnostic Panel, OnkoMatch, University of Washington – OncoPlex-Cancer Gene Panel) are considered investigational except for the evaluation of members diagnosed with non-small-cell lung cancer to guide cancer treatment. There is insufficient published data to determine the impact on health outcomes of targeted treatment based on expanded tumor marker panels compared to standard of care for cancer types other than non-small-cell lung cancer.
(NOTE: For use of Guardant360 in patients with non-small-cell lung cancer, please refer to a separate policy on 'Circulating Tumor DNA for Management of Non-Small-Cell-Lung Cancer (Liquid Biopsy)' - Policy #136 in the Pathology Section.)
2. FoundationOne CDx is medically necessary as an FDA-approved companion diagnostic test for any of the following FDA-approved targeted therapies:
| Indication |
| Therapy |
Non-small cell lung cancer
(NSCLC) |
EGFR exon 19 deletions and EGFR exon 21
L858R alterations
| Gilotrif® (afatinib),
Iressa® (gefitinib), or
Tarceva® (erlotinib) |
|
EGFR exon 20 T790M alterations
| Tagrisso® (osimertinib) |
|
| Alecensa® (alectinib),
XALKori® (crizotinib), or
Zykadia® (ceritinib) |
|
| Tafinlar® (dabrafenib) in combination with Mekinist® (trametinib) |
| Melanoma |
| Tafinlar® (dabrafenib) or
Zelboraf® (vemurafenib) |
|
| Mekinist® (trametinib) or
Cotellic® (cobimetinib) in combination with Zelboraf® (vemurafenib) |
| Breast cancer |
ERBB2 (HER2) amplification
| Herceptin® (trastuzumab),
Kadcyla® (ado-trastuzumabemtansine), or
Perjeta® (pertuzumab) |
| Colorectal cancer |
KRAS wild-type (absence of mutations in codons 12 and 13)
| Erbitux® (cetuximab) |
|
KRAS wild-type (absence of mutations in exons 2, 3, and 4) and NRAS wild type (absence of mutations in exons 2, 3, and 4)
| Vectibix® (panitumumab)
|
| Ovarian cancer |
| Rubraca® (rucaparib) |
Medicare Coverage:
Per NCD 90.2, effective for services performed on or after March 16, 2018, Next Generation Sequencing (NGS) as a diagnostic laboratory test is covered 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. The individual has:
· either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; and,
· 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,
· decided to seek further cancer treatment (e.g., therapeutic chemotherapy).
2. The diagnostic laboratory test using NGS must have:
· Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,
· an FDA-approved or -cleared indication for use in that patient’s cancer; and,
· results provided to the treating physician for management of the patient using a report template to specify treatment options.
Additionally, effective for services performed on or after March 16, 2018, Medicare Administrative Contractors (MACs) may determine coverage of other NGS as a diagnostic laboratory test for individuals with cancer when NCD 90.2 criteria is met.
For additional information and eligibility, refer to NCD National Coverage Determination (NCD) for Next Generation Sequencing (NGS) (90.2). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.
PROPRIETARY LABS (Labs that are the sole source for the diagnostic lab test)
For labs which are proprietary (that is, the sole source for the diagnostic lab test involved), Medicare Advantage Products will follow the Medicare Local Coverage Determination of the State where the proprietary lab is located.
In addition, Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has made determinations for certain Next Generation Sequencing (NGS) tests. Please refer to Novitas Solutions Inc, LCD Biomarkers for Oncology (L35396) for eligibility and coverage. Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46
Local Coverage Determination (LCD): BRCA1 and BRCA2 Genetic Testing (L36715). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.
On 1/27/20, CMS issued Decision Memo for Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer (CAG-00450R) with additional coverage for next generation sequencing. Per Decision memo CAG-00450R, the Centers for Medicare & Medicaid Services (CMS) has determined that Next Generation Sequencing (NGS) as a diagnostic laboratory test is reasonable and necessary and covered nationally, when performed in a CLIA-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:
1. The individual has:
· ovarian or breast cancer; and
· a clinical indication for germline (inherited) testing for hereditary breast or ovarian cancer; and
· a risk factor for germline (inherited) breast or ovarian cancer; and
· was not been previously tested with the same germline test using NGS for the same germline genetic content.
2. The diagnostic laboratory test using NGS must have all of the following:•
· Food and Drug Administration (FDA) approval or clearance; and
· results provided to the treating physician for management of the individual using a report template to specify treatment options
CMS also provided that Medicare Administrative Contractors (MACs) may determine coverage of Next Generation Sequencing (NGS) as a diagnostic laboratory test when performed in a CLIA-certified laboratory, when ordered by a treating physician, when results are provided to the treating physician for management of the individual and when the individual has:
· any cancer diagnosis; and
· a clinical indication for germline (inherited) testing of hereditary cancers; and
· a risk factor for germline (inherited) cancer; and
· has not been previously tested with the same germline test using NGS for the same germline genetic content.
[INFORMATIONAL NOTE: The National Comprehensive Cancer Network (NCCN) provides the following types of guidance.
o NCCN Guidelines for Treatment of Cancer by Site provide detailed guidelines on the use of individual tumor markers for each cancer type addressed.
o NCCN also makes the following recommendations specifically for using multigene panels in the evaluation of non-small cell lung cancer (NSCLC): “The NCCN NSCLC Guidelines Panel strongly endorses broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.”
o NCCN has not recommended a panel approach for any other cancer types as of mid-2017.
o NCCN also maintains a biomarker compendium stating “the goal of the NCCN Biomarkers Compendium is to provide essential details for those tests which have been approved by NCCN Guideline Panels and are recommended by the NCCN Guidelines.”4 Biomarkers for specific cancer types that are listed in the NCCN Biomarker Compendium have a level of evidence associated with their clinical utility.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies
Molecular Panel Testing of Cancers to Identify Targeted Therapies
FoundationOne CDx Test
FoundationOne CDx Heme Test
TruSeq Amplicon Panel
TruSight
AmpliSeq
Ion AmpliSeq Comprehensive Cancer Panel
Ion AmpliSeq Cancer Hotspot Panel
OnkoMatch Gene Panel
GeneTrails Solid Tumor Panel
Caris Life Sciences Tumor Profiling Services
SmartGenomics Cancer-Associated Genes
Guardant360
Paradigm Cancer Diagnostic Panel
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
MSK-IMPACT
Illumina Cancer Panels
Life Technologies Cancer Panels
Knight Diagnostic Labs Solid Tumor Panel
GenPath Diagnostics PCR-Based Gene Panel
FoundationOne CDx
References:
1. NCI. Tumor markers. Available at: http://www.cancer.gov/about-cancer/diagnosisstaging/diagnosis/tumor-markers-fact-sheet
2. National Comprehensive Cancer Network. 2016 Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. V7.2017: Available at:http://www.nccn.org/professionals/physician_gls/pdf/nscl_blocks.pdf
3. US Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. Available at:http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
4. National Comprehensive Cancer Network. NCCN Biomarkers Compendium. Available at: http://www.nccn.org/professionals/biomarkers/content/
5. National Comprehensive Cancer Network. NCCN Guidelines for Treatment of Cancer by Site. Available at:http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
6. Sturgeon CM, Hoffman BR, Chan DW, et al.; National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in clinical practice: quality requirements. Clin Chem. 2008 Aug:54(8)e1-e10.
7. US Food and Drug Administration. FoundationOne CDx Technical Information. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019C.pdf
8. US Food and Drug Administration. List of cleared or approved companion diagnostic devices. Available at:https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm
9. US Food and Drug Administration. Approval Order for the Oncomine Dx Target Test. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160045A.pdf
10. National Comprehensive Cancer Network. 2016 Clinical Practice Guidelines in Oncology: Colon Cancer. V2.2017: Available at:http://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf
11. National Comprehensive Cancer Network. 2016 Clinical Practice Guidelines in Oncology: Melanoma. V1.2017: Available at:http://www.nccn.org/professionals/physician_gls/pdf/melanoma_blocks.pdf
12. US Food and Drug Administration. FoundationOne CDx Technical Information. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019C.pd
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
[If a panel meets the requirements for one of the specific CPT codes for targeted genomic sequence analysis panel (81445-81455), the code may be reported for the test.
If the panel does not meet the requirements for a CPT panel code, any specific mutation which is listed in the codes 81200-81409 would be reported using those codes and the other mutations in the panel which are not specifically listed would be reported with 1 unit of the unlisted molecular pathology code 81479.]
HCPCS
* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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