Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

POLICY NUMBER

A.2.04.115

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 policy. Rather, this policy 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.

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 benefits. It is unusual for cancer treatment to be effective for all patients treated in a traditional clinical trial. Spear and colleagues analyzed the efficacy of major drugs used to treat several important diseases. 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. These may be categorized into three classes: (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 policy. 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 policy also does not address the use of cancer-specific panels that include a few variants. Rather, this policy 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 one potentially pathogenic variant. 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 2015 study, 439 patients with diverse cancers were tested with a 236-gene panel. A total of 1,813 molecular alterations were identified, and almost all patients (420/439 [96%]) had at least one molecular alteration. The median number of alterations per patient was 3, and 85% of patients (372/439) had two 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. There are several examples of variant-directed treatment that is effective in one 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 in 2015 by Hyman and colleagues. 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

The table below provides a select list of commercially available expanded cancer molecular panels.

Commercially Available Molecular Panels for Solid and Hematologic Tumor Testing

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

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 the table below. 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." Food and Drug Administration 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.

Companion Diagnostic Indications for F1CDx

F1CDx: FoundationOne Companion Diagnostic.¹An 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 . 

Related policies -

• Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer

• Molecular Analysis for Targeted Therapy or Immunotherapy of Non-Small-Cell Lung Cancer

• Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer

• Somatic Genetic Testing To Select Individuals with Melanoma or Glioma for Targeted Therapy or Immunotherapy

• Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

POLICY

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

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

07/17/2014: Approved by Medical Policy Advisory Committee.

08/04/2015: Code Reference section updated for ICD-10.

11/11/2015: Policy title changed from "Molecular Panel Testing of Cancers to Identify Targeted Therapies" to "Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies." Policy description updated regarding expanded cancer mutation panels. Policy statement unchanged. Investigative definition updated in policy guidelines section.

12/31/2015: Code Reference section updated to new 2016 CPT codes 81219, 81272, 81273, 81314, 81535, 81536, and 81538.

06/07/2016: Policy number A.2.04.115 added.

11/07/2016: Policy description updated regarding genetic markers and to list commercially available expanded cancer mutation panels. Policy statement unchanged.

10/27/2017: Policy description updated regarding expanded cancer molecular panels. Policy statement updated to change "mutation" to "molecular." Policy Guidelines updated to add genetics nomenclature update.

12/21/2017: Code Reference section updated to add new 2018 CPT codes 81175 and 81176.

03/27/2018: Code Reference section updated to add new CPT code 0037U, effective 04/01/2018.

10/31/2018: Policy description revised to update list of molecular panels for solid and hematologic tumor testing. Policy statement unchanged.

07/01/2019: Code Reference section updated to add new CPT code 0092U.

01/09/2020: Policy title changed from "Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies" to "Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies." Policy description updated regarding companion diagnostic indications for F1CDx. Policy statement updated to change "expanded cancer molecular panels" to "comprehensive genomic profiling." Policy intent unchanged.

06/25/2020: Code Reference section updated to add new CPT code 0174U, effective 07/01/2020.

11/20/2020: Policy description updated regarding molecular panels and companion diagnostic indications for F1CDx. Policy statement unchanged.

03/25/2021: Code Reference section updated to add new CPT code 0244U, effective 04/01/2021.

06/29/2021: Code Reference section updated to add new CPT codes 0249U and 0250U, effective 07/01/2021.

09/29/2021: Code Reference section updated to add new CPT code 0262U, effective 10/01/2021.

12/16/2021: Code Reference section updated to add new CPT code 0296U, effective 01/01/2022.

01/12/2022: Policy description updated regarding commercially available molecular panels for solid and hematologic tumor testing and companion diagnostic indications for F1CDx. Policy statement unchanged. Policy Guidelines updated to remove genetics nomenclature.

06/27/2022: Code Reference section updated to add new CPT code 0329U, effective 07/01/2022.

09/12/2022: Code Reference section updated to add new CPT code 0334U, effective 10/01/2022.

12/07/2022: Policy description updated regarding companion diagnostic indications for F1CDx. Updated related medical policies. Policy statement unchanged.

12/19/2022: Code Reference section updated to add new CPT codes 81449, 81451, and 81456, effective 01/01/2023.

09/25/2023: Code Reference section updated to add new CPT codes 0404U and 0409U, effective 10/01/2023.

11/10/2023: Policy description updated regarding the following: 1) Commercially available molecular panels for solid and hematologic tumor testing; 2) Companion diagnostic indications for F1CDx. Policy statement unchanged.

12/21/2023: Code Reference section updated to revise the code descriptions for CPT codes 81449, 81451, and 81456, effective 01/01/2024.

03/27/2024: Code Reference section updated to add new CPT code 0444U, effective 04/01/2024.

10/01/2024: Code Reference section updated to add new CPT code 0511U.

12/13/2024: Policy description updated regarding the following: 1) molecular panels for solid and hematologic tumor testing; and 2) companion diagnostic indications for F1CDx. Policy statement unchanged.

04/01/2025: Code Reference section updated to add new CPT codes 0538U and 0543U, effective 04/01/2025.

07/18/2025: Code Reference section updated to add new CPT code 0562U. Effective 07/01/2025.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.115

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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