PROPOSED/DRAFT Local Coverage Determination (LCD):
MolDX: NSCLC, Comprehensive Genomic Profile Testing (DL36198)
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Please note: This is a Proposed/Draft policy.
Proposed/Draft LCDs are works in progress that are available on the Medicare Coverage Database site for public review. Proposed/Draft LCDs are not necessarily a reflection of the current policies or practices of the contractor.
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| CONTRACTOR NAME | CONTRACT TYPE | CONTRACT NUMBER | JURISDICTION | STATE(S) |
|---|---|---|---|---|
| Noridian Healthcare Solutions, LLC | A and B MAC | 02102 - MAC B | J - F | Alaska |
| Noridian Healthcare Solutions, LLC | A and B MAC | 02202 - MAC B | J - F | Idaho |
| Noridian Healthcare Solutions, LLC | A and B MAC | 02302 - MAC B | J - F | Oregon |
| Noridian Healthcare Solutions, LLC | A and B MAC | 02402 - MAC B | J - F | Washington |
| Noridian Healthcare Solutions, LLC | A and B MAC | 03102 - MAC B | J - F | Arizona |
| Noridian Healthcare Solutions, LLC | A and B MAC | 03202 - MAC B | J - F | Montana |
| Noridian Healthcare Solutions, LLC | A and B MAC | 03302 - MAC B | J - F | North Dakota |
| Noridian Healthcare Solutions, LLC | A and B MAC | 03402 - MAC B | J - F | South Dakota |
| Noridian Healthcare Solutions, LLC | A and B MAC | 03502 - MAC B | J - F | Utah |
| Noridian Healthcare Solutions, LLC | A and B MAC | 03602 - MAC B | J - F | Wyoming |
Document Information
Title XVIII of the Social Security Act, §1862(a)(1)(A)allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member
Title XVIII of the Social Security Act, §1862(a)(1)(D) items and services related to research and experimentation
Title XVIII of the Social Security Act, §1833(e), prohibits Medicare payment for any claim which lack the necessary information to process the claim.
42 CFR 410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions
42CFR411.15(k)(1) Particular services excluded from coverage
CMS On-Line Manual, Publication 100-08, Medicare Program Integrity Manual, Chapter 3, §3.4.1.3, diagnosis code requirements
Title XVIII of the Social Security Act, §1862(a)(1)(D) items and services related to research and experimentation
Title XVIII of the Social Security Act, §1833(e), prohibits Medicare payment for any claim which lack the necessary information to process the claim.
42 CFR 410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions
42CFR411.15(k)(1) Particular services excluded from coverage
CMS On-Line Manual, Publication 100-08, Medicare Program Integrity Manual, Chapter 3, §3.4.1.3, diagnosis code requirements
Coverage Indications, Limitations, and/or Medical Necessity
This policy provides limited coverage for comprehensive somatic genomic profiling on tumor tissue-only (hereafter called CGP) for patients with metastatic non-small cell lung cancer (NSCLC) who are lifetime non-smokers (also known as never-smokers) or former light smokers (=15 pack year history) and who tested negative for epidermal growth factor receptor (EGFR) mutations, EML4-ALK rearrangements, and ROS1 rearrangements when initial testing was done by an FDA-approved companion diagnostic (CDx) or by a laboratory developed test (LDT) for these genomic alterations. Alterations detected by CGP, if positive, may allow individuals to be treated with a targeted therapy for which they were previously ineligible. At the current time, CGP for germline (i.e. inheritable) mutations is not a Medicare benefit.
Background
It is estimated that more than 220,000 new cases of lung cancer will be diagnosed in the United States (US) this year. This represents roughly 13% of all new cancer diagnoses, and 27% of cancer deaths. Sadly, the estimated 5-year survival rate for all lung cancer patients is 17%, and only 4% for patients with metastatic disease.
The pathophysiological development of lung cancer is complicated, with several known genomic alterations found individually or in combination in many patients. These alterations may be due to toxic exposure or underlying genetic factors, and not all alterations have the same impact on disease development or prognosis. Some alterations appear to be integral to the transformation and ongoing growth of the tumor (driver mutations). Among the best studied in this class are point alterations and indels in EGFR and EML4-ALK translocations. EGFR mutated NSCLC is found in up to 15% of all lung cancers in the US. These mutations convey a more favorable prognosis and allow treatment with oral EGFR inhibitors such as erlotinib, gefitinib, or afatinib. Similarly, translocations of ALK and EML4 or other less common fusion partners occur in approximately 4% of all NSCLC patients and permit treatment with oral ALK-targeted inhibitors such as crizotinib and ceritinib.
The majority of NSCLC cases are diagnosed in patients with a smoking history. Lifetime non-smokers or light former smokers (=15 pack years) have different disease compared to their heavier smoking counterparts. Sequencing of tumor specimens in never-smokers has shown a higher mutation frequency of EGFR than smokers, with some non-smoking ethnic groups such as Asian women having a much higher mutation frequency than their Caucasian counterparts. Similar results have been shown with ALK translocations. For example, in one study involving never-smokers or light smokers with adenocarcinoma of the lung, 22% of patients’ tumors harbored an ALK. When EGFR mutation carriers were excluded, 33% of patients had an ALK translocation. While ALK translocations and EGFR mutations certainly occur at a meaningful frequency in former smokers with more significant history of cigarette use, use of the enrichment approach described herein may allow a more efficient completion of this initial phase of study.
Currently, a variety of different techniques are used to test for these genomic alterations in tumor specimens including three FDA cleared/approved CDx tests for NSCLC to determine if a patient is a candidate for targeted therapy. For EGFR, there is the Cobas® EGFR Mutation Test for erlotinib and Therascreen EGFR RCQ PCR Kit for afatinib. For ALK, there is the Vysis ALK Break Apart FISH Probe Kit for crizotinib. These tests look at specific regions in the target gene to determine if the genomic alteration of interest is present.
In addition to these FDA-approved CDx test, there are a variety of laboratory-developed tests (LDTs) that are used to identify EGFR mutations and ALK translocations. These include bidirectional Sanger sequencing, direct DNA sequencing, hybridization sequencing, pyrosequencing and sequencing by denaturation to name a few. Some of these LDTs provide more extensive genetic analysis than their FDA-approved counterparts, but there are few head-to-head comparison studies demonstrating greater diagnostic accuracy or clinical utility of the various approaches.
For various reasons, CDx or LDT sequencing techniques may miss deleterious EGFR mutations and ALK translocations. For example, alterations may occur outside the sequenced region or involve complex alterations (e.g. insertions or deletions (indels), copy number alterations, or translocations) that are not detectable by the specific test. Newer techniques such as massively parallel sequencing, also known as next generation sequencing (NGS), offer the possibility of not only increased analytical sensitivity but also the ability to detect a broader range of genomic alterations than existing CDx and LDT techniques.
In a recent study by Drilon, lifetime non-smokers or light smokers who tested negative for alterations in various target genes (including EGFR and ALK) in a broad “focused panel of a variety of non-NGS” tests developed at a major academic institution were studied using a specific type of NGS, namely CGP. Despite robust non-NGS (and CGP) testing using multiple techniques, CGP testing identified EGFR mutations in 7% more patients than had been identified by prior combined methodologies, and 6% more ALK translocations than by previous FISH analysis. Although some of the EGFR mutated malignancies found by NGS are less likely to respond to available EGFR tyrosine kinase inhibitors (TKIs) (e.g. exon 20 insertions), others such as complex double mutations and exon 18 mutations (which are typically undetectable with so-called “hotspot” panels), are likely to benefit from targeted therapy. CGP analysis was equally compelling for ALK translocations. In two patients, where FISH analysis was clearly negative, translocations were identified using CGP. These patients would likely benefit from treatment with crizotinib.
Although the study population is small, the significant number of potentially actionable genomic alterations that were missed by non-NGS methodologies is compelling, and demonstrates that CGP can identify a group of non- small cell lung cancer patients who are likely to benefit from targeted therapy.
Comprehensive Genomic Profiling (CGP) Test Description:
CGP analysis is defined as a single test using tumor tissue only (i.e., not matched tumor and normal) that does not distinguish between somatic and germline alterations and can detect the following classes of alterations:
Other non-NGS testing platforms may be considered if they can similarly detect all four classes of alterations with comparable test performance as CGP.
MolDX CGP Analysis Coverage
CGP analysis is covered only when the following conditions are met:
Noridian expects participating laboratories to:
This policy provides limited coverage for comprehensive somatic genomic profiling on tumor tissue-only (hereafter called CGP) for patients with metastatic non-small cell lung cancer (NSCLC) who are lifetime non-smokers (also known as never-smokers) or former light smokers (=15 pack year history) and who tested negative for epidermal growth factor receptor (EGFR) mutations, EML4-ALK rearrangements, and ROS1 rearrangements when initial testing was done by an FDA-approved companion diagnostic (CDx) or by a laboratory developed test (LDT) for these genomic alterations. Alterations detected by CGP, if positive, may allow individuals to be treated with a targeted therapy for which they were previously ineligible. At the current time, CGP for germline (i.e. inheritable) mutations is not a Medicare benefit.
Background
It is estimated that more than 220,000 new cases of lung cancer will be diagnosed in the United States (US) this year. This represents roughly 13% of all new cancer diagnoses, and 27% of cancer deaths. Sadly, the estimated 5-year survival rate for all lung cancer patients is 17%, and only 4% for patients with metastatic disease.
The pathophysiological development of lung cancer is complicated, with several known genomic alterations found individually or in combination in many patients. These alterations may be due to toxic exposure or underlying genetic factors, and not all alterations have the same impact on disease development or prognosis. Some alterations appear to be integral to the transformation and ongoing growth of the tumor (driver mutations). Among the best studied in this class are point alterations and indels in EGFR and EML4-ALK translocations. EGFR mutated NSCLC is found in up to 15% of all lung cancers in the US. These mutations convey a more favorable prognosis and allow treatment with oral EGFR inhibitors such as erlotinib, gefitinib, or afatinib. Similarly, translocations of ALK and EML4 or other less common fusion partners occur in approximately 4% of all NSCLC patients and permit treatment with oral ALK-targeted inhibitors such as crizotinib and ceritinib.
The majority of NSCLC cases are diagnosed in patients with a smoking history. Lifetime non-smokers or light former smokers (=15 pack years) have different disease compared to their heavier smoking counterparts. Sequencing of tumor specimens in never-smokers has shown a higher mutation frequency of EGFR than smokers, with some non-smoking ethnic groups such as Asian women having a much higher mutation frequency than their Caucasian counterparts. Similar results have been shown with ALK translocations. For example, in one study involving never-smokers or light smokers with adenocarcinoma of the lung, 22% of patients’ tumors harbored an ALK. When EGFR mutation carriers were excluded, 33% of patients had an ALK translocation. While ALK translocations and EGFR mutations certainly occur at a meaningful frequency in former smokers with more significant history of cigarette use, use of the enrichment approach described herein may allow a more efficient completion of this initial phase of study.
Currently, a variety of different techniques are used to test for these genomic alterations in tumor specimens including three FDA cleared/approved CDx tests for NSCLC to determine if a patient is a candidate for targeted therapy. For EGFR, there is the Cobas® EGFR Mutation Test for erlotinib and Therascreen EGFR RCQ PCR Kit for afatinib. For ALK, there is the Vysis ALK Break Apart FISH Probe Kit for crizotinib. These tests look at specific regions in the target gene to determine if the genomic alteration of interest is present.
In addition to these FDA-approved CDx test, there are a variety of laboratory-developed tests (LDTs) that are used to identify EGFR mutations and ALK translocations. These include bidirectional Sanger sequencing, direct DNA sequencing, hybridization sequencing, pyrosequencing and sequencing by denaturation to name a few. Some of these LDTs provide more extensive genetic analysis than their FDA-approved counterparts, but there are few head-to-head comparison studies demonstrating greater diagnostic accuracy or clinical utility of the various approaches.
For various reasons, CDx or LDT sequencing techniques may miss deleterious EGFR mutations and ALK translocations. For example, alterations may occur outside the sequenced region or involve complex alterations (e.g. insertions or deletions (indels), copy number alterations, or translocations) that are not detectable by the specific test. Newer techniques such as massively parallel sequencing, also known as next generation sequencing (NGS), offer the possibility of not only increased analytical sensitivity but also the ability to detect a broader range of genomic alterations than existing CDx and LDT techniques.
In a recent study by Drilon, lifetime non-smokers or light smokers who tested negative for alterations in various target genes (including EGFR and ALK) in a broad “focused panel of a variety of non-NGS” tests developed at a major academic institution were studied using a specific type of NGS, namely CGP. Despite robust non-NGS (and CGP) testing using multiple techniques, CGP testing identified EGFR mutations in 7% more patients than had been identified by prior combined methodologies, and 6% more ALK translocations than by previous FISH analysis. Although some of the EGFR mutated malignancies found by NGS are less likely to respond to available EGFR tyrosine kinase inhibitors (TKIs) (e.g. exon 20 insertions), others such as complex double mutations and exon 18 mutations (which are typically undetectable with so-called “hotspot” panels), are likely to benefit from targeted therapy. CGP analysis was equally compelling for ALK translocations. In two patients, where FISH analysis was clearly negative, translocations were identified using CGP. These patients would likely benefit from treatment with crizotinib.
Although the study population is small, the significant number of potentially actionable genomic alterations that were missed by non-NGS methodologies is compelling, and demonstrates that CGP can identify a group of non- small cell lung cancer patients who are likely to benefit from targeted therapy.
Comprehensive Genomic Profiling (CGP) Test Description:
CGP analysis is defined as a single test using tumor tissue only (i.e., not matched tumor and normal) that does not distinguish between somatic and germline alterations and can detect the following classes of alterations:
- Base pair substitutions (including single nucleotide variants (SNVs))
- Insertions and deletions (Indels; up to 70 bp)
- Copy number variations (CNVs; including both amplifications (ploidy < 4 with copy number = 8) and homozygous deletions (ploidy < 4 with copy number = 0)
- Translocations
Other non-NGS testing platforms may be considered if they can similarly detect all four classes of alterations with comparable test performance as CGP.
MolDX CGP Analysis Coverage
CGP analysis is covered only when the following conditions are met:
- Patient has been diagnosed with advanced (Stage IIIB or IV) NSCLC; and
- Patient is a lifetime non-smoker or former light smoker with =15 pack year history of smoking; and
- Patient previously tested negative for EGFR mutations, ALK rearrangements, and ROS1 rearrangements through non-CGP methods; and
- Testing is performed by a lab that satisfies the MolDX Contractor's published AV criteria.
Noridian expects participating laboratories to:
- Prior to CGP testing, verify that each patient has previously tested negative for EGFR mutations, ALK
rearrangements, and ROS1 rearrangements - Report the following to MolDX every six months on an individual patient basis but de-identified (i.e., no protected health information):
- Patient demographics including patient age when the specimen was collected, and gender;
- Sample information including whether CGP testing was performed on the same specimen DNA as the original test result, a re-biopsy from the same tumor site, or a re-biopsy from a different tumor site, and the dates of biopsy for the original non-CGP and CGP tests;
- Non-CGP test methodology resulting in a negative EGFR mutations, or ALK or ROS1 rearrangements;
- Alterations in the following genes: ALK, BRAF, EGFR, HER2, KRAS, MET, ROS1, and RET.
- Any treatment received after CGP testing, the current response status and duration of response
- Reports will be delivered every 6 months in a mutually acceptable format.
Associated Information
N/A
Sources of Information and Basis for Decision
Please refer to the attachment titled, "References" found at the bottom of this LCD.
Open Meetings/Part B MAC Contractor Advisory Committee (CAC) Meetings
Comment Period Start Date| MEETING DATE | MEETING TYPE | MEETING STATE(S) | MEETING INFORMATION |
|---|---|---|---|
| 06/04/2015 | Open Meeting |
| Noridian Headquarters – Room W3 900 42nd St S Fargo, ND 58103 |
06/04/2015
Comment Period End Date
08/10/2015
Released to Final LCD Date
02/03/2016
Reason for Proposed LCD- Creation of Uniform LCDs With Other MAC Jurisdiction
Proposed Contact
Noridian Healthcare Solutions, LLC JF Part B Contractor Medical Director(s)
Policy Development - Medicare Part B - Drafts
900 42nd Street S., PO Box 6704
Fargo, ND 58108 policyb.drafts@noridian.com
Policy Development - Medicare Part B - Drafts
900 42nd Street S., PO Box 6704
Fargo, ND 58108 policyb.drafts@noridian.com
Bill Type Codes:
Contractors may specify Bill Types to help providers identify those Bill Types typically used to report this service. Absence of a Bill Type does not guarantee that the policy does not apply to that Bill Type. Complete absence of all Bill Types indicates that coverage is not influenced by Bill Type and the policy should be assumed to apply equally to all claims.
| 013x | Hospital Outpatient |
| 014x | Hospital - Laboratory Services Provided to Non-patients |
Revenue Codes:
CPT/HCPCS Codes
Contractors may specify Revenue Codes to help providers identify those Revenue Codes typically used to report this service. In most instances Revenue Codes are purely advisory. Unless specified in the policy, services reported under other Revenue Codes are equally subject to this coverage determination. Complete absence of all Revenue Codes indicates that coverage is not influenced by Revenue Code and the policy should be assumed to apply equally to all Revenue Codes.
| 0300 | Laboratory - General Classification |
| 0301 | Laboratory - Chemistry |
| 0309 | Laboratory - Other Laboratory |
| 0310 | Laboratory Pathology - General Classification |
Group 1 Paragraph: N/A
Group 1 Codes:
| 81445 | TARGETED GENOMIC SEQUENCE ANALYSIS PANEL, SOLID ORGAN NEOPLASM, DNA ANALYSIS, 5-50 GENES (EG, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), INTERROGATION FOR SEQUENCE VARIANTS AND COPY NUMBER VARIANTS OR REARRANGEMENTS, IF PERFORMED |
| 81455 | TARGETED GENOMIC SEQUENCE ANALYSIS PANEL, SOLID ORGAN OR HEMATOLYMPHOID NEOPLASM, DNA AND RNA ANALYSIS WHEN PERFORMED, 51 OR GREATER GENES (EG, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), INTERROGATION FOR SEQUENCE VARIANTS AND COPY NUMBER VARIANTS OR REARRANGEMENTS, IF PERFORMED |
| 81479 | UNLISTED MOLECULAR PATHOLOGY PROCEDURE |
ICD-10 Codes that Support Medical Necessity
Group 1 Paragraph: N/A
Group 1 Codes:
| ICD-10 CODE | DESCRIPTION |
|---|---|
| C33 | Malignant neoplasm of trachea |
| C34.01 | Malignant neoplasm of right main bronchus |
| C34.02 | Malignant neoplasm of left main bronchus |
| C34.11 | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.31 | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.81 | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | Malignant neoplasm of overlapping sites of left bronchus and lung |
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