Response to Comments: MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Targeted Therapy in Cancer A60509 Article

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

On behalf of the Association for Molecular Pathology (AMP), thank you for the opportunity to comment on the draft Local Coverage Determination (dLCD) entitled MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer.

AMP is an international medical and professional association representing approximately 3,100 physicians, doctoral scientists, and medical laboratory scientists (technologists) who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from academic medicine, hospital-based and private clinical laboratories, the government, and the in-vitro diagnostics industry. AMP members are highly involved in the development, validation, and interpretation of molecular diagnostic tests, including targeted molecular panel tests for predictive testing in cancer patients.

AMP greatly appreciates that MolDX proposed favorable coverage of non-next-generation sequencing (NGS) based targeted molecular panel tests for predictive testing in cancer. Tests of this kind, including those that evaluate a single, actionable biomarker, are often instrumental for rapid decision-making purposes when time is of the essence, as is the case for many patients with cancer.

AMP members with expertise in this type of testing have identified several changes outlined in the information below that will help streamline the policy and ensure practitioners are able to order and provide this essential testing to patients.

Coverage Indications, Limitations, and/or Medical Necessity

Removal of NGS Requirement in National Guidelines

AMP is concerned that the current wording in Criterion 2b conflicts with the phrasing used in national consensus guidelines. There is currently no specification stating NGS must (or must not) be used as the initial testing methodology. Most oncology guidelines recommend the use of next generation sequencing (NGS), but do not explicitly require it.¹

Additionally, the following sentence in 2b is unclear and vague “testing by a non-NGS method will provide a rapid result that allows for the prompt and timely management of the patient”. As there is no definition of rapid result within the coverage policy nor is there a general definition understood by practitioners.

As such, AMP requests that the following definitions be clarified:

- “required by national consensus guidelines”

- “rapid result”

This will allow providers to have a better understanding of the limitations in this coverage policy. If no such definitions exist, AMP strongly recommends deleting Criterion 2b, as the current language introduces unnecessary ambiguity that could lead to confusion among providers and potential gaps in patient care.

AMP Seeks Clarification on the Standard Ordering Practices of Providers

When ordering genetic tests, the standard practice, in many cases, requires health practitioners to order both a non-NGS test and an NGS panel concurrently, recognizing each method offers a distinct and complementary purpose. As such, Criterion 3 does not align with standard practice. For example, when rapid treatment decisions are needed based on actionable biomarkers, providers may order targeted single-gene tests to guide treatment decisions while simultaneously ordering NGS panels to capture broader genomic information. The time saved in the NGS process is invaluable when determining cancer prognosis, diagnosis, and treatment options.^2,3

As such, AMP recommends that the red text with the strikethrough is deleted from criterion 3:

“The patient has not been previously tested by a molecular panel test for the same cancer indication for the same genetic content.

This deletion would allow concurrent ordering of non-NGS tests for actionable biomarkers and NGS panels for comprehensive profiling, without creating unnecessary administrative or coverage barriers.

Standard for “Comparable” Accuracy is Undefined

AMP is also concerned with Criterion 6, which requires the accuracy of non-NGS testing to be “comparable” to that of NGS methods. Next generation sequencing is a newer technology that is increasing in accuracy every year as it advances. It is impossible to continually have two methods be “comparable” as the technologies deviate. Therefore, AMP recommends that this criterion be removed as any further definition has a high likelihood of becoming out of date as technology advances.

Remove Redundant Criteria

AMP recommends removing Criterion 8, as the content is duplicative of the requirements already outlined in the Technical Assessment process. The focus of the coverage criteria should be on outlining coverage and medical necessity for testing, not repeating standards addressed within the technical assessment.

Additionally, if MolDX chooses to maintain Criterion 8, we strongly urge you to revise the following sentence:

“Clinical validity (CV) of any analytes or profiles must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population with demonstrated reproducibility across clinical study cohorts.”

The current language could be misinterpreted to mean that each laboratory must independently publish clinical studies for tests already supported by published evidence. We recommend clarifying that laboratories are not required to generate or publish their own CV data if such evidence already exists in the literature.

If Criterion 8 remains in the final LCD, we urge consistent language across all LCDs, ensuring that these criteria do not impose requirements more stringent than those found in existing technical assessment forms.

Thank you again for the opportunity to review and comment on this draft policy. We are happy to provide additional clinical or other information to assist you as you work towards finalizing the LCD.

References and redline draft were provided for review.

Sincerely,

Jane S. Gibson, PhD

President, Association for Molecular Pathology

Thank you for your comment and support of this LCD. We respond as follows:

• Criterion 2:

• We have modified “Required by national consensus guidelines” for clarity and to more accurately reflect the language of the guidelines.
• The concept of a “rapid result” is further defined in the criterion (“less than the ASCO-recommended 10 business days from sample receipt in the laboratory”).

• We disagree that standard of practice requires a non-NGS panel and an NGS panel to be ordered concurrently. Standard of practice in many cases is to order PCR for select genes with known targeted, actionable therapies and to order an NGS panel when the former yields a negative result. Such targeted testing, when positive and informative, will often obviate the need for an NGS panel. Moreover, rapid targeted panel tests (such as PCR panels) can provide results in a matter of hours to days and thus inform the need for a subsequent NGS panel in a timely manner when it is necessary for the subsequent management of the patient. We note that ordering both NGS and non-NGS panels concurrently for the same cancer indication and genetic content is considered by this contractor to be duplicative testing and not reasonable and necessary.
• Comparable or superior performance to NGS is expected for those analytes that are measured by both methodologies. We do not apply prohibitively rigid criteria to this effect, but it is not in the interest of patient care to settle for tests with substantially inferior performance.
• While the criterion relevant to clinical validity aligns with other requirements, it remains an essential requirement that merits explicit emphasis as a core coverage criterion. Further, nowhere in the LCD does it state that laboratories are required to generate or publish their own CV data if such evidence already exists in the peer-reviewed published literature for the same analytes and intended uses.

The following comment was submitted to Palmetto GBA and WPS:

General Comment in Support of Proposed LCD

Timely access to biomarker test results for patients with cancer prior to first line treatment remains a significant challenge in clinical practice. While recent data show a continuing improvement over time, the rate of improvement remains slow, with fewer than 50% of patients with advanced stage cancer receiving biomarker data prior to treatment initiation¹.

Regardless of the methodology used, we firmly support all efforts to improve patient access to high quality biomarker testing and to overcome the barriers that too often prevent timely access to targeted treatments.

By offering providers additional options for biomarker testing, proposed LCD presents an opportunity to overcome challenges associated with limited or poor-quality samples, and with slow turnaround time of test results. The Criteria for Coverage laid out in the proposed LCD, along with the coverage of reflex NGS testing in the event of negative results from smaller targeted panels, offer strong and adequate protections to patients against the risk of false negative results due to limited coverage of targeted panels, without risking delays to treatment.

We wholeheartedly support the adoption of this proposed LCD, and applaud MolDx for their efforts to improve patient access to vital biomarker information.

Suggestions and Requests for Amendments

1. Criteria for Coverage (6):

As correctly stated in the Summary of Evidence, multiple professional bodies, including AMP, CAP, and IASLC stipulate that genomic results should be available within 10 business days after sample receipt in the laboratory, as also recommended by ASCO. The wording in Criterion 6 states ‘10 business days from sample acquisition’, which we are concerned could be inferred as from the date on which the sample is obtained from the patient, introducing an element that is out of the control of the test provider. To avoid confusion we suggest amending this criterion to align with the Summary of Evidence text and to state ‘from receipt of sample in the testing laboratory’.

2. Completeness of Biomarker Coverage Using NGS

The Summary of Evidence quite correctly states that NGS-based testing is the most comprehensive approach to broad-based molecular profiling, and has the ability to interrogate multiple different types of genomic alterations. However, we are concerned that the text may be interpreted to mean that all NGS tests provide comprehensive coverage of all guideline recommended genomic biomarkers, or that they all provide broader biomarker coverage than non-NGS approaches, when this is sometimes not the case. Specific examples of this include the following:

1. oncoReveal CDx (Pillar Biosciences) does not include coverage of ROS1, RET, or NTRK1/2/32
2. FoundationOne CDx (Foundation Medicine) does not include coverage of gene fusions in NTRK33
3. LungSEQ Concurrent (Quest) does not include coverage of gene fusions in NTRK1/2/34

It is also important to note that many NGS assays interrogate only DNA, resulting in poor detection of gene fusions, with data published by MSK indicating that as many as 25% of gene fusions can be missed by DNA analysis alone⁵. Another study has also demonstrated that breakpoints identified by DNA analysis do not always lead to in-frame fusion transcripts and so are unreliable for predicting the efficacy of targeted therapy⁶.

To avoid misinterpretation, we suggest that the Summary of Evidence be amended to clarify that biomarker coverage varies between NGS assays, and that not all NGS assays provide comprehensive coverage of guideline recommended biomarkers for all indications.

3. Summary of Evidence of Aspyre^TM

In recent months several additional journal articles have been published which describe the technical performance of the Aspyre Lung assay, and we request that the Summary of Evidence text be updated to reflect this.

In particular we note three peer reviewed journal articles; one authored by the University of Pennsylvania describing a multi-site concordance study and including challenging cytology sample types⁷, and two describing the performance of the assay on liquid biopsy samples^8,9 including at low nucleic acid input quantities where the assay demonstrated significantly higher sensitivity than leading NGS-based assays¹⁰. We also note a bridging validation study conducted in accordance with CAP/CLIA guidelines which assessed the performance of the assay at low input mass using FFPE-derived nucleic acids, demonstrating consistent sensitivity at high or low input mass, which was presented as a conference abstract at AACR 2025¹¹.

We suggest the following amended wording in this section of the Summary of Evidence:

Aspyre (Allele-Specific Pyrophosphorolysis REaction) Lung (Biofidelity, Cambridge, UK), is a multi-step enzymatic amplification method^12,13 that enables the concurrent detection of 114 genetic alterations (77 detected by DNA and 37 by RNA, in a single workflow) across 11 genes from paired DNA (5-20 ng) and RNA (1.5-6 ng) derived from FFPE lung tissue, or from paired cfDNA (5-20ng) and cfRNA (6-42ng) derived from blood plasma.

In a peer-reviewed analytical validation and concordance study authored by the manufacturer, comparison of Aspyre Lung results against NGS using 30 FFPE samples from NSCLC patients along with contrived reference material demonstrated 100% positive percentage agreement (PPA) and 100% negative percentage agreement (NPA), 100% repeatability and reproducibility, and 100% specificity¹⁴. Aspyre Lung achieved variant specific and panel-wide limits of detection (LOD) of ≤3% for SNVs and indels, ≤100 copies for fusions, and ≤200 copies for MET exon 14 skipping. The test can be performed on samples with ≥10% tumor purity and has a TAT from sample extraction to analysis of approximately two days¹⁵.

In a further study conducted by the University of Pennsylvania and the Medical College of Wisconsin⁷, Aspyre Lung was performed at three independent sites using nucleic acids derived from 61 FFPE tissue and 16 cytology samples, including peritoneal fluid, pleural effusions, and fine needle aspirates (FNAs). Reproducibility data for all 77 patient samples yielded a PPA of 100% and NPA of 99.99%, while concordance with NGS yielded 97.2% PPA and 99.96% NPA. Three discordant calls between the assay and NGS were observed. In one sample a ROS1 fusion was detected by Aspyre Lung across all three sites, but was not detected by the orthogonal NGS assay. Subsequent analysis of this sample using RNA sequencing confirmed the presence of this fusion, implying a false negative result from the original NGS assay. One sample was called as positive for MET exon14 skipping by NGS at a level below the limit of detection of Aspyre Lung, and was not called by Aspyre, while a third sample harbored a rare ALK fusion not present in the Aspyre Lung panel.

Two additional peer-reviewed publications authored by the manufacturer have demonstrated the application of Aspyre Lung on cell-free nucleic acids derived from blood plasma^8,9. At 20ng cfDNA and 42ng cfRNA input the LOD of the assay was established at ≤0.25% VAF for SNVs, ≤0.4% VAF for indels, ≤6 copies for gene fusions, and ≤100 copies for MET exon 14 skipping events, while at low nucleic acid input (5ng cfDNA, 6ng cfRNA), the LOD was ≤0.8% for SNVs and indels, ≤6 copies for gene fusions, and ≤100 copies for MET exon 14 skipping, exceeding the sensitivity levels of many NGS assays at reduced input mass10. Specificity of the assay was 100%. A comparison with NGS using 32 cfDNA and 32 cfRNA samples derived from 44 different patients with a confirmed diagnosis of NSCLC along with a set of contrived reference material yielded a PPA of 94% and NPA of 100%.

We thank the MolDx team for their consideration of these suggestions.

References were provided for review.

Sincerely,

Barnaby Balmforth

Chief Executive Officer Biofidelity

Thank you for your comment and support of this LCD. We respond as follows:

• To better align with the recommendation by the professional bodies as noted in the Summary of evidence, we have amended the language to “less than the ASCO-recommended 10 business days from sample receipt in the laboratory.”
• We agree that not all NGS tests provide comprehensive coverage of all guideline-recommended genomic biomarkers. For clarity, we have revised the language in the Summary of Evidence accordingly.
• Summary of Evidence of Aspyre^TM: We have included additional information and publications relevant to the Aspyre^TM tests.

The following comment was submitted to Palmetto GBA and Noridian:

Why is 81479 the only code on the proposed LCA?

The letter from Padma Sundar at Chromacode mentions the HDPCR multi-gene molecular profiling assay and there is a DEX entry for Lung HDPCR™ Panel with Z code and recommended CPT code: 0478U. Will 0478U be added to the article?

The letter from Anjana Bhattacharya as Biofidelity does not mention a specific test, however the DEX entry for this lab has 3 tests listed and only ONE of them has 81479 listed as the recommended CPT code: Aspyre Clinical Test for Lung - Tissue (RNA only). The other tests are:

Aspyre Clinical Test for Lung – Blood: 81462

Aspyre Clinical Test for Lung – Tissue: 81445

Will either of these CPT codes be added to the policy?

Thank you for your time,

Kerry Haas, MS, CGC

Senior Genetic Counselor | Research and Development

Thank you for your comment.

At this time, we have not included additional CPT codes in the Billing Article.

Note that listing of codes in the Billing Article does not imply coverage of those codes. The LCD requirements must be met, including a successful Technical Assessment of the relevant tests, prior to determination of whether those codes are deemed in compliance with the LCD.

The following comment was submitted to Palmetto GBA:

I am writing to express my support for Draft Local Coverage Determination (LCD) and to respectfully request that the coverage criteria be broadened to include genomic expression signatures in addition to the technologies currently addressed in the policy.

As a pathologist and clinical laboratory director specializing in genomics and oncology, I commend MolDX for its commitment to timely, evidence-based access to molecular diagnostics. Draft LCD thoughtfully addresses the real-world need for rapid, accurate results that guide therapy selection, particularly when NGS is infeasible or slow.

At the same time, the draft’s apparent focus on non-NGS driver panels to detect actionable mutations and fusions may unintentionally exclude clinically validated, predictive genomic expression signatures that answer equally critical treatment questions.

Notably, Draft LCD highlights the risk of worse outcomes when immune checkpoint inhibitors (ICIs) are used or sequenced sub-optimally. Predictive Immuno-oncology biomarkers derived from genomic expression profiles could directly mitigate this risk by supporting appropriate therapeutic sequencing, thereby helping clinicians avoid ineffective or harmful ICI use.

If not already contemplated in the existing draft LCD, we respectfully request that MolDX revise the policy to allow for the inclusion of predictive genomic expression profiling tests, provided they meet the same rigorous evidentiary standards already established in the policy (e.g., analytical validity, clinical validity, clinical utility, and compliance with MolDX technical assessment).

Suggested edit to the coverage criteria:

We recommend editing requirement 4 to expand applicability to qualifying tests:

4. The test accurately detects the most common genes and genomic positions or employs a validated multi-gene signature for the identification of clinically relevant FDA-approved therapies for the given cancer type.

Broadening the language in this manner would ensure equitable access to all clinically validated molecular diagnostic modalities, including genomic expression-based assays.

Thank you for the opportunity to comment on this important policy.

Sincerely,

Pranil K. Chandra, D.O.

Medical Director

Insight Molecular Diagnostics

Thank you for your comment and support of this LCD.

The test must comply with all components of the LCD and that includes that “The test accurately detects the most common genes and genomic positions required for the identification of clinically relevant FDA-approved therapies with a companion diagnostic biomarker for the given cancer type.”

“Or employs a validated multi-gene signature” would not fulfill the language and intent of this policy.

However, a test that fulfills policy criteria that also includes predictive information regarding the response to immunotherapy would be considered under this LCD.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

I am writing on behalf of the American Clinical Laboratory Association (ACLA) to provide comments on the draft Local Coverage Determination MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer¹ (“dLCD”). ACLA is the national trade association representing leading laboratories that deliver essential diagnostic health information to patients and providers by advocating for policies that expand access to the highest quality clinical laboratory services, improve patient outcomes, and advance the next generation of personalized care. Many ACLA member laboratories submit claims to Medicare Administrative Contractors (MACs) that follow MolDX policies and have an interest in the program’s coverage determinations and operations.

ACLA member laboratories are greatly concerned about the scope, intentions, and impact of the dLCD as drafted on coverage for both non-Next Generation Sequencing and Next-Generation Sequencing (NGS) tests. If MolDX proceeds with finalizing this dLCD, it is crucial that numerous issues are resolved, including the impact on covered NGS testing, concerning and confusing “Criteria for Coverage”, and the impact of “bundling”:

1. Impact on NGS Testing

ACLA is concerned that a request for an LCD for a specific test platform has been used to develop an “umbrella” policy with far-reaching implications beyond the original request. Further, the association is concerned that if the dLCD is finalized as drafted, it would have a negative impact on the appropriate utilization and coverage of NGS tests, and it potentially could increase the turnaround time for NGS test results if it is used to justify a step-wise testing approach (discussed later in this letter). ACLA agrees that non-NGS molecular tests can be appropriate for Medicare beneficiaries and should be considered for coverage, but providing a coverage pathway for these tests should not negatively impact current coverage for NGS tests.

Consider, for example in a recent large-scale claims analysis, more than 40% of metastatic cancer patients had no molecular testing of any kind before the second line of therapy, representing a crisis of underutilization for guideline-recommended biomarker assessment. Care should be taken to avoid an indirect detrimental impact on utilization of NGS testing which is best suited to genotype patients with minimal specimen use.²

2. Specific Concerns with “Criteria for Coverage”

1. Second Criterion for Coverage

ACLA is concerned with key aspects of the “criteria for coverage.” First, the requirement that “Testing by next-generation sequencing (NGS) is not feasible or will likely fail based on specimen type or tumor content” is confusing, as the language in the dLCD serves only to distinguish “non-NGS” tests from “NGS” tests. A scenario in which NGS testing is truly “not feasible” is clinically rare. In fact, multiple “non-NGS” tests would be necessary to address all guideline-recommended biomarkers for any specific solid cancer, including the six associated with FDA-approved therapies across all solid tumors. Tumor Mutation Burden, for example, guides FDA-approved immunotherapy in patients and is assessed via NGS technology. Studies have shown that when compared to NGS testing, patients receiving non-NGS tests are less likely to have complete genotyping of guideline-recommended biomarkers.³ For example, a recent large-scale claims analysis showed that metastatic cancer patients with NGS testing for 50 genes or greater had higher rates of targeted treatment (Non-Small Cell Lung Cancer (NSCLC) and Colorectal Cancer (CRC)), while costs were not significantly different for patients with breast cancer, CRC, gastric cancer, NSCLC, pancreatic cancer, and ovarian cancer compared to those patients receiving testing under 50 genes.⁴

While not discussed in the dLCD, liquid biopsy and circulating tumor DNA (ctDNA) tests are “NGS” tests that are recommended for use when traditional somatic tumor biomarker testing would not be appropriate for the patient due to specimen type or tumor content. The lack of discussion regarding liquid biopsy in this section is confusing, as the criterion regarding specimen type or tumor content is potentially applicable only for tissue-based testing, as NGS testing approaches more efficiently genotype cancers with available specimen compared to multiple individual “non-NGS” tests. Additionally, guidelines now recommend that liquid biopsy testing should be performed concurrently to ensure that crucial treatment decisions are informed with a quick turn-around-time. It is unclear why MolDX neglected to include any discussion of the evolution of NGS tests in the Summary of Evidence or consider in the criteria for coverage how NGS tests are used currently.

Second, the requirement “NGS is not required by national consensus guidelines to inform medical management decisions AND testing by a non-NGS method will provide a rapid result that allows for the prompt and timely management of the patient,” also is concerning. At least 26 National Comprehensive Cancer Network (NCCN) guidelines include NGS or comprehensive molecular profiling as a testing approach for recommended biomarkers. In fact, esophageal and gastric guidelines state “sequential testing... or use of limited molecular diagnostic panels may exhaust the sample”, prostate guidelines state “testing using a next-generation sequencing (NGS) assay ... is preferred”, and Colon/Rectal guidelines state “testing may be carried out for individual genes or as part of an NGS panel, with NGS being preferred.” Furthermore, in 2022, the American Society of Clinical Oncology (ASCO) issued a “strong” recommendation for all patients with advanced solid tumors to receive multigene panel testing when more than one genomic biomarker is linked to an approved therapy. This statement defined multigene panel as “an NGS test that sequences a defined list of genes with at least 50 genes in total”.⁵

In general, “national consensus guidelines that inform medical management decisions” do indicate specific genetic alterations that will impact treatment decisions; however, they frequently do not specify the individual test or technology that should be employed to assess the presence of these alterations. We anticipate it would be difficult for laboratories and providers to prove that NGS was or was not definitively required by these guidelines. Additionally, as mentioned above, all “NGS” tests are not identical and, similar to “non-NGS tests”, have varying turn-around-times.

Third, ACLA has concerns about the requirement “The test accurately identifies known, common, and necessary predictive and actionable biomarkers that can safely preclude unnecessary NGS testing, reducing NGS use in patients for whom the treatment plan would not likely be altered,” (emphasis ours). As noted above, ACLA has concerns about the negative sentiment regarding the use of NGS tests throughout the dLCD, which is evident in this requirement. It is unclear to laboratories how the MAC would define “unnecessary NGS testing” and also how a laboratory would prove that one test technology was more “safe” or appropriate than another. Furthermore, the criterion alludes to a clinical scenario in which a series of smaller tests would impact treatment but an NGS test containing the same content would not. Studies have demonstrated that NGS testing not only completely genotypes patients more frequently (see earlier references) but also directs patients to clinical trials from which they benefit,⁶ in addition to identifying rare mutations not present on many “non-NGS tests” as reflected within NCCN guidelines for several cancer types. We anticipate that these vague thresholds would result in varying application of the dLCD across MACs, with negative reimbursement implications for laboratories that perform either “non-NGS” or “NGS” testing for a given patient. Non-NGS testing should be held to the same standard as NGS panels, requiring "at least the minimum genes" and equivalent performance to established NGS testing.

To address ACLA’s concerns, we respectfully recommend that MolDX make the following redline edits to the Second Criteria for Coverage, which should address the motivation for the development of the coverage policy (i.e., the flexibility for physician choice for non-NGS testing, when appropriate, and the rare clinical scenarios where rapid turn-around time is crucial) while avoiding the procedural issues in the currently drafted criterion:

1. Third Criterion for Coverage

ACLA is concerned about the implications of the requirement “The patient has not been previously tested by a molecular panel test for the same cancer indication for the same genetic content. NOTE: A negative result (no clinically actionable mutations found) by the non-NGS test may be followed by an NGS test that includes additional necessary non-duplicative genes and genomic positions.”

This requirement could be read to restrict the usage of “NGS tests” (covered by other LCDs) by introducing a new requirement that a “non-NGS test” should be performed first, with an “NGS” test following only if the “non-NGS test” provided a negative result. This application of the requirement is in conflict with many cancer guidelines and the ASCO 2022 “strong” recommendation that NGS testing be performed. There is no cancer guideline support for tiered testing approaches as outlined in this third criterion.

Beyond the implications for NGS tests, we are concerned that this restriction also would narrow the potential uses for “non-NGS” tests. For example, one potential use of a “non-NGS molecular test” would be to assess a small number of genes for a new mutation following a change in response to treatment in a cancer patient who previously had an “NGS molecular test” to determine the patient’s initial treatment at diagnosis. We anticipate that the current wording of this restriction would prevent usage of these “non-NGS” tests for this reason.

If MolDX elects to include a restriction regarding repeat testing, ACLA recommends that this language be struck and replaced by the requirement from the MolDX: Next-Generation Sequencing for Solid Tumors LCD⁷: “The patient has not been previously tested by the same test for the same genetic content.”

3. Fourth Criterion for Coverage

While the Coverage Guidance explains that the draft policy “describes and clarifies coverage for molecular or proteomic panel tests for Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer”, the fourth criterion as currently worded applies only to molecular non-NGS panels.

In order to ensure that the coverage criteria can be used for either molecular or proteomic panel tests, ACLA respectfully recommends the following redline edits to criterion 4:

At least one of the following is true:

1. The test accurately detects the most common genes and genomic positions required for the identification of clinically relevant FDA-approved therapies with a companion diagnostic biomarker for the given cancer type.
2. The test accurately detects protein signatures that guide clinically relevant FDA-approved immunotherapy-based treatment options for the given cancer type.

4. Sixth Criterion for Coverage

It is unclear how the MAC intends to operationalize the sixth criterion for coverage: “The test demonstrates accuracy for measured analytes comparable to NGS testing, with superior turnaround times less than the ASCO-recommended 10 business days from sample acquisition,” (emphasis ours). Inherent to this criterion is the assumption that a non-NGS test will have “superior” turnaround times, but this may not be reflective of clinical care, especially given the multiple non-NGS tests that must be performed to genotype all guideline-recommended biomarkers. Additionally, non-NGS testing on tumor tissue or multiple tests on blood or a mix of specimen types imposes unnecessary delays resulting from specimen acquisition and coordination. Turnaround times for tests can vary based on numerous factors outside either the laboratory or the ordering provider’s control. The established turnaround times for many commercial NGS tests are below 10 days, with some liquid biopsy NGS testing as low as 5 days. Patients are more likely to receive a targeted treatment as a first line therapy when NGS testing is performed, especially by liquid biopsy NGS testing, where turnaround time is rapid.⁸ We are concerned that a decision either to cover or non-cover a test would be dependent on a variable component (i.e. turn-around time), as opposed to the utility of the test for a given patient. Additionally, it is unclear if the MAC intends to monitor turnaround time for each test and deny payment for tests which are equal to or longer than 9 days or if the MAC intends to assess the criteria this using some other mechanism.

ACLA respectfully recommends that the sixth criterion for coverage be edited to read as follows: “The test demonstrates accuracy for the measured analytes comparable to NGS testing.”

1. Seventh Criterion for Coverage

ACLA notes that the seventh criterion is worded differently than similar MolDX LCDs: “The test has satisfactorily completed a Technical Assessment (TA) by the Molecular Diagnostic Services Program (MolDX^®) to ensure analytical validity (AV), clinical validity (CV) and clinical utility (CU) standards are met,” (emphasis ours). This is the first LCD that explicitly states “AV, CV, and CU standards” must be met through the MolDX TA process for coverage. It is our understanding that services covered under similar LCDs have inherent CU as determined by the contractor.

3. Concerns about Bundling

In addition, ACLA has concerns about language regarding bundling. The last line of the dLCD reads: “Finally, this contractor considers the testing service in its entirety, and notes that multiple assays may be required to constitute a singular service.” ACLA is concerned that such a broad statement would result in payment for laboratory tests covered under the policy that differ from the rates established by the Centers for Medicare & Medicaid Services (CMS). Additionally, ACLA believes that the option for the MAC to “bundle” any services provided on the same day would increase the confusion regarding NGS and non-NGS services discussed in detail above. To prevent further confusion, ACLA urges MolDX to strike the last line of the dLCD copied above.

Finally, ACLA members are concerned that this statement could create confusion regarding coverage requirements and lead to high rates of claim denials by Medicare Advantage (MA) plans that require laboratories to use Z-codes for claims submissions. Laboratories note that some MA plans that require Z-codes also currently require individual submission of test claims in all cases and do not have the ability to process bundled claims.

Medicare coverage policies should be based upon clinical effectiveness, patient-centered outcomes, and adaptability to emerging evidence—ensuring that care remains inclusive, flexible, and responsive to diverse medical needs and evolving technologies. ACLA respectfully suggests focusing on the patient population, intended use of testing and how it improves/drives patient care and outcomes, rather than a specific technology or group of technologies.

ACLA welcomes the opportunity to engage in a collaborative discussion with you and your team about the recommendations above. Thank you for your attention to our concerns.

References and redline drafts were provided for review.

Sincerely,

Sarah Thibault-Sennett, PhD

Senior Director, Reimbursement Policy American Clinical Laboratory Association

Thank you for your comment. Please see Response #1. Also, note that some Criteria have been renumbered and consolidated, where appropriate. Additionally -

• The scope of this LCD is limited to Non-Next Generation Sequencing Targeted Molecular Panel Tests for Targeted Therapy in Cancer. The LCD is foundational such that multiple tests may fall within the scope of this policy. For clarity, we have removed the singular instance of the word “proteomic” in the draft LCD but note may fall within scope of this LCD if ALL criteria are met. Note that tests are defined as “Proteomic” in accordance with A59641, Billing and Coding: MolDX: Proteomics Testing.
• Impact of turnaround time is addressed in the LCD and in our response above. Finally, the coverage of NGS tests is described in separate MolDX LCDs; however, the current LCD also references the appropriate use-cases for panel testing by non-NGS within the broader context of appropriate NGS utilization.
• The current LCD specifically acknowledges and highlights the concern regarding the “crisis of underutilization for guideline-recommended biomarker assessment” and addresses it by providing another avenue for patients to receive reliable, rapid and actionable results.
• We agree that testing by NGS will often provide the most comprehensive information regarding guideline-recommended biomarkers. However, this is not always true and depends on both the specific NGS test performed and the tumor type (e.g., tumor mutational burden profiling is not required for all tumor types). It is also true that in recent years, non-NGS panel tests have become more comprehensive, as noted in the LCD.
• Guideline inclusion of NGS or comprehensive molecular profiling as a possible testing approach is not equivalent to a guideline recommendation. Further, inclusion of molecular profiling in guidelines may be relevant to uses other than directly informing targeted therapy (such as prognostication), which is the explicit intended use outlined in this LCD. For added clarity, we have modified the LCD title. We further note that multigene panel testing does not only apply to NGS panels and agree that guidelines do not always specify the recommended individual tests or technologies that should be employed.
• The perception that a “non-NGS test” should always be performed first is not accurate. Additionally, we note that coverage of testing by NGS is currently restricted by NCD 90.2 to include only Medicare beneficiaries with recurrent, relapsed, refractory, metastatic, or advanced cancers.
• Liquid biopsy testing is addressed by the LCD criteria as it constitutes another “panel” test - The patient has not been previously tested by a molecular panel test for the same cancer indication for the same genetic content. The criterion does not state that the panel test must be a tissue-based test. Therefore, if a liquid biopsy test has already been performed for the same cancer indication and genetic content, then a non-NGS panel test would not be R&N per policy. Additionally, the current LCD is not intended to review the evidence for liquid biopsies and note that MolDX has already published an LCD for plasma profiling of solid tumors.
• The use of a “non-NGS molecular test” to assess a small number of genes for a new mutation following a change in response to treatment in a cancer patient who previously had an “NGS molecular test” to inform initial treatment is not precluded by this LCD. An a priori suspicion for a new mutation denotes a change in genetic content.
• The evaluation of a test’s stated clinical utility is part of every technical assessment.
• We agree that specimen exhaustion and eligibility for clinical trials are essential considerations regarding the choice of panel test and have added relevant language to the LCD.

The panel test is the service, regardless of the number of assays performed. The service as a whole must be Reasonable and Necessary in accordance with the LCD. 

The following comment was submitted to Palmetto GBA:

On behalf of OncoHost, Inc., I appreciate the opportunity to provide public comment on MolDX’s Proposed LCD (“MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer”). OncoHost supports the finalization of this Proposed LCD to “describe[] and clarif[y] coverage for molecular or proteomic panel tests for Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer.”

As the developing and performing laboratory of the PROphetNSCLC test, our unique plasma proteome-based personalized test designed to support first-line treatment selection in metastatic non-small cell lung cancer, we respectfully request certain adjustments to the Proposed LCD. Specifically, we request changes to confirm that it accommodates proteomic tests like PROphetNSCLC to predict the likelihood of clinical benefit when a patient is treated with a guideline-approved PD-1/PD-L1 inhibitor alone or in combination with chemotherapy in the first line setting. We believe these minor changes will help ensure that the LCD provides a broad and flexible framework for review of non-NGS tests to inform cancer treatment.

We look forward to the opportunity to meet after the conclusion of the comment period.

Background on PROphetNSCLC

OncoHost’s PROphetNSCLC test is a plasma proteome-based personalized test for first-line treatment selection in metastatic non-small cell lung cancer that uses machine learning to identify proteins that are associated with clinical benefit from immunotherapy-based regimens. Despite over a decade of immune checkpoint inhibitors (ICIs) being approved for use in the treatment of metastatic non-small cell lung cancer, many patients are unable to achieve clinical benefit from these therapies.¹ Patients are exposed to the potential additional toxicities of immunotherapy with the hope of having a durable response and many durable responders are exposed to chemotherapy unnecessarily.² Current tissue-based biomarkers have limited predictive efficacy in addition to technical barriers to implementation.

Plasma proteomics can interrogate the tumor, host, and the microenvironment, and provide patient level information complementary to the tumor-based biomarkers, such as programmed death-ligand (PD-L1) to inform ICI based treatment decisions. PROphetNSCLC™ is the only proteomics-based machine learning test that provides the probability of clinical benefit when treated with a guideline approved PD-1/PD-L1 inhibitor alone or in combination with chemotherapy in the first-line setting. The PROphetNSCLC™ test is intended for use as a treatment decision tool in the management of newly diagnosed stage IV non-small cell lung cancer (NSCLC) patients being considered for treatment with PD-1/PD-L1 inhibitors in the first-line setting.

PROphetNSCLC™ is supported by a substantial body of clinical evidence. The PROphetNSCLC test model was designed using a selected cohort of 500 patients enrolled on the PROPHETIC trial—an international prospective and retrospective clinical trial (NCT04056247) who were treated with an ICI. The study cohorts include a diverse population from the United States of America (USA), Europe and the Middle East, treated according to the current standard of care, and is representative of a real-world population with prolonged follow up. The patients were partitioned into development (n=228) and validation sets (n=272). The algorithm that determined the PROphet Score was trained and then blindly validated according to FDA’s Good Machine Learning Practices to minimize risks for overfitting and data leakage (Christopoulos et al., 2024a). The trial demonstrated that PROphet status was strongly associated with clinical benefit (R² = 0.98, P < .001), and the test provided predictive value beyond standard PD-L1 expression and TMB status.

Notably, a decision impact study conducted with 100 US practicing oncologists using virtual patients with metastatic NSCLC tumors of varying PD-L1 levels (PD-L1 > 50%, 1-49%, <1% and either a PROphet “positive” or “negative” result) showed that 93% of physicians changed treatment recommendation from their baseline recommendation in at least one of the six PROphetNSCLC tested cases.³

PROphetNSCLC is performed for US patients only in OncoHost’s CLIA certified laboratory in Cary, North Carolina. The test has been assigned CPT 0436U⁴ by the CPT Editorial Panel.

Support Finalization of Proposed LCD Encompassing Molecular and Proteomic Tests

OncoHost strongly supports the finalization of Proposed LCD. We agree that the benefits of “broad molecular testing to inform the use of targeted therapies in cancer…need not be derived solely from testing by NGS.”

Furthermore, OncoHost strongly supports MolDX’s stated proposal to use the policy to “describe[] and clarif[y] coverage for molecular or proteomic panel tests.” We agree that many of the same considerations supporting the reasonableness and necessity of non-NGS tests to inform cancer treatment—such as less complexity and better suitability for first-line testing, capability to be performed on smaller specimens, and shorter turnaround time—apply equally to molecular and to proteomic tests.

PROphetNSCLC exemplifies many of these benefits of non-NGS testing to predict the success of cancer treatment. First, PROphetNSCLC is a more appropriate first-line testing option than NGS for a large subset of metastatic NSCLC patients, and, indeed, a significant segment of cancer patients overall. In a study by Haslam and Prasad published in JAMA Network Open in 2019, it was estimated that, as of 2018, 43.6% of US cancer patients were eligible for checkpoint inhibitor drugs, with NSCLC representing 21.48% of the total eligible population. More recent analyses suggest that overall ICI eligibility in the U.S. may have reached over 55% by 2023. A meta-analysis reports that only about 20%⁵ of NSCLC patients benefit from immunotherapy, stressing that many individuals—especially those without driver mutations—still experience meaningful clinical responses.

PROphetNSCLC helps to guide first-line treatment for these patients by predicting an individual’s probability of clinical benefit from PD-1/PD-L1 inhibitors. As discussed above, a study conducted with 100 US practicing oncologists using virtual patients with metastatic NSCLC tumors of varying PD-L1 levels (PD-L1 >50%, 1-49%, <1%), evaluating treatment recommendations before and after the addition of a PROphetNSCLC Test result, demonstrated significant treatment decision impact. A total of 93% of physicians changed treatment recommendation from their baseline recommendation in at least one of the 6 PROphet tested cases. Treatment was changed by 89% of physicians in PD-L1 High > 50% PROphet tested cases (95% CI: 81.4-93.7), 77% in PD-L1 negative (<1%) PROphet tested cases (95%CI 67.8-84.2), and 36% in PD-L1 1-49% PROphet tested cases (95% CI:27.3-45.8). Treatment changes were more common when the PROphet result was NEGATIVE compared to POSITIVE (61.8% vs. 38.2%) (Gandara et al,. 2024).

An overview of the impact of PROphetNSCLC results on suggested PD-1/PD-L1 suggested treatment is below. This demonstrates the clear, actionable clinical guidance derived from the predictive results of the test.

Furthermore, PROphetNSCLC is performed on a plasma specimen, making collection far easier than for tissue specimen-based NGS tests. PROphetNSCLC’s turnaround time of 7-10 days is also substantially superior to most NGS-based tests⁶.

Given the Proposed LCD’s stated inclusion of proteomic testing, and the alignment of certain proteomic tests like PROphetNSCLC with the stated reasons in the LCD for covering non-NGS methodologies for predictive testing in cancer, we respectfully encourage MolDX, in finalizing the LCD, to make any technical modifications to the LCD language (in addition to the modification described below to the coverage criteria) necessary to clarify the inclusion of proteomic tests.

Technical Modifications to Coverage Criteria to Ensure Inclusion of Proteomic Tests

OncoHost supports the coverage criteria proposed by MolDX and views them as striking the appropriate balance between rigorous standards and the flexibility necessary to allow MolDX to review a broad category of cancer testing through the TA process. As we will discuss in the Appendix, we believe that PROphet would meet all but one of the draft coverage criteria. We urge minor revisions to Criterion 4 to ensure that the Final LCD remains available for the adjudication of TAs for proteomic tests.

As proposed, Criterion 4 requires that “[t]he test accurately detects the most common genes and genomic positions required for the identification of clinically relevant FDA-approved therapies with a companion diagnostic biomarker for the given cancer type.” The requirement to accurately detect “the most common genes and genomic positions” would render this criterion impossible for a proteomic test to satisfy, thereby undermining the stated purpose of the Proposed LCD to “describe[] and clarif[y] coverage for molecular or proteomic panel tests.”

Accordingly, we recommend modifying Criterion 4 to add the following parallel Criterion 4.b: “The test accurately detects protein signatures demonstrated to guide the selection of clinically relevant FDA-approved therapies.” The “demonstrated to guide” language ensures that a proteomic test is supported by evidence showing that it impacts the oncologist’s decision as to whether to utilize a clinically relevant FDA-approved therapy, similar to the role played by the “required to identify” language for genes and genomic positions in the current Criterion 4.

We believe this standard will ensure that the inclusion of proteomic tests in the LCD is manageable by setting clear evidentiary requirements for decision impact. The PROphetNSCLC test would satisfy this standard because the proteomic signature provided by PROphetNSCLC has been demonstrated to guide the selection of appropriate therapies within PD-L1 categories.

Conclusion

For the foregoing reasons, OncoHost encourages MolDX to finalize with technical modifications to ensure that the policy can satisfy its stated objective of setting coverage criteria for molecular and proteomic tests alike. In particular, we respectfully request changes to Criterion 4 so that the finalized LCD is sufficiently flexible to cover well-validated proteomic tests like PROphetNSCLC, which has been demonstrated to impact treatment selection for patients who have undergone PD-L1 testing.

As you are aware, we submitted an LCD request with an extensive evidence packet in September 2024. We are reattaching the clinical dossier that was submitted with our LCD request, which includes references to the full-text articles previously sent. In addition, we are including the following peer-reviewed publication, which was published after the submission of our LCD request: Decoding resistance to immune checkpoint inhibitors in non-small cell lung cancer: a comprehensive analysis of plasma proteomics and therapeutic implications⁷. This paper adds biological and clinical explainability to the machine learning algorithm of the PROphetNSCLC.

We appreciate your review and request the opportunity to meet after the conclusion of the comment period. Please do not hesitate to contact us if you have any questions or need additional information.

References, image, appendix, and clinical dossier were provided for review.

Sincerely,

Ofer Sharon, M.D. CEO

OncoHost, Inc.

Response 6:

Thank you for your comment and support of this LCD. Please see our Responses above.

The following comment was submitted to Palmetto GBA, CGS, Noridian, and WPS:

The National Comprehensive Cancer Network^® (NCCN^®) appreciates the opportunity to comment on the Proposed Local Coverage Determination (LCD) MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer as it relates to NCCN's mission of defining and advancing quality, effective, equitable, and accessible cancer care and prevention so all people can live better lives. NCCN will focus our comments on ways NCCN content can be used as a resource to inform coverage determinations, keep LCDs evergreen as the science evolves, and ensure Medicare beneficiaries have access to the highest standard of care possible.

NCCN Background

As an alliance of 33 leading academic cancer centers in the United States (US) that treat hundreds of thousands of patients with cancer annually, NCCN^® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, survivorship care, palliative care, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the US.

NCCN Guidelines^® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. The NCCN Drugs & Biologics Compendium has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related

NCCN Guidelines^® and Biomarker Compendium^®

NCCN develops authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Guidelines are a comprehensive set of 88 guidelines detailing the sequential management decisions and interventions across 228 algorithms that currently apply to 97 percent of cancers affecting patients in the United States. More than 1,950 panel members participate in guideline development. In 2024, there were 16 million downloads of NCCN Guidelines across web-based and mobile applications. The guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 241 total version updates across all guidelines in 2024.

The NCCN Guidelines are considered the standard for clinical care and policy in oncology in the United States. The NCCN Guidelines are the most thorough and most frequently updated clinical practice guidelines in any area of medicine, are the most frequently referenced clinical practice guideline in oncology, and are widely available free of charge for non-commercial use. Our guidelines are also available through a multitude of health information technology vendors, used by payers representing more than 85% of covered lives in the United States, and form the basis for insurance coverage policy and quality evaluation.

To further support evidence-based decision making, NCCN also offers companion resources such as the NCCN Biomarkers Compendium^®. NCCN Biomarkers Compendium^® serves as a resource for payers, providers, and health care entities navigating the rapidly changing evidence­ base for medically necessary biomarker testing in oncology. It contains information derived directly from the NCCN Guidelines to support clinical decision-making around the use of biomarker testing in patients with cancer. The Biomarker Compendium is updated continuously in conjunction with the NCCN Guidelines to stay evergreen. Included in the Biomarkers Compendium are testing methodologies to measure changes in genes or gene products and used for the purposes of diagnosis, screening, monitoring, surveillance, treatment planning, prediction, and prognostication. The NCCN Biomarker Compendium focuses largely on the biology or abnormality being measured rather than on commercially available tests or test kits.

Importantly, NCCN imposes strict policies to shield the guidelines development processes from external influences. The "firewall" surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN's other business development activities. The guidelines development is supported exclusively by the Member Institutions' dues and does not accept any form of industry or other external financial support for the guidelines development program.

Guideline Adherence as a Tool to Improve Outcomes, Reduce Costs, and Keep Coverage Evergreen

Numerous independent studies have found adherence to NCCN Guidelines improve care delivery and outcomes for patients with cancer. Improved health outcomes proven through concordance with NCCN Guidelines include improved rates of survival for colon cancer, ovarian cancer, gastric cancer, nasopharyngeal cancer, and pancreatic cancer; decreased locoregional recurrence of melanoma; and improved pain control. ^1,2,3,4,5,6

Guideline adherent care has also been shown to decrease costs to both the payer and the patient. A peer-reviewed, published study by United, eviCore, and NCCN entitled "Transforming Prior Authorization to Decision Support" demonstrated mandatory adherence to NCCN Guidelines and NCCN Compendium^® using a real-time Clinical Decision Support Mechanism by United Healthcare significantly reduced total and episodic costs of care by 20% compared to trend while also reducing denials and increasing access to guideline-concordant care.⁷ A 2019 study "Guideline Discordance and Patient Cost Responsibility in Medicare Beneficiaries With Metastatic Breast Cancer" by Williams, et.al found median cost for metastatic breast cancer patients receiving guideline-discordant treatment was $7,421 versus $5,171 for those receiving guideline-concordant care.⁸ This study found an additional $1,841 in out-of-pocket cost savings for patients receiving guideline concordant care versus patients who received care that did not adhere to guidelines. These cost savings have also been found in studies evaluating the Medicare population. At the 2022 ASCO Annual Meeting, CVS Health also presented two abstracts looking at total costs of care beginning with the first treatment and for the subsequent 180 days for breast and colon cancer patients in relation to adherence to NCCN Guidelines·^9,10 In both studies, there was a significant reduction in total cost of care with concordance with NCCN Guidelines. In the colon cancer study, this was most prominent and significant in the Medicare population. In the breast cancer study, significant reductions were observed across both commercially insured and Medicare patients, with the greatest reductions again seen in the Medicare population.

Recognizing the value of guidelines that are continuously updated and proven to reduce costs while improving outcomes, numerous Medicare Administrative Contractors have cited NCCN guidelines within their coverage policies as a mechanism for coverage. These policies include Palmetto's Local Coverage Article: Billing and Coding: Chemotherapy, Wisconsin Physician Services' LCD Chemotherapy Drugs and their Adjuncts, and National Government Services' Genomic Sequence Analysis Panels in the Treatment of Solid Organ Neoplasms among others. NCCN recommends that MolDX consider the incorporation of nationally recognized guidelines into the proposed MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer LCD coverage indications in order to ensure the LCD stays evergreen in offering Medicare beneficiaries optimal and evidence-based care.

NCCN Guideline References within the LCD and Areas for Clarification

NCCN thanks MolDX for referencing NCCN content within the proposed LCD. NCCN will provide commentary and further insight into the current NCCN Guidelines recommendations as they relate to Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer.

Within the Summary of Evidence section, MolDX states:

"The National Comprehensive Cancer Network (NCCN) and ASCO guidelines recommend broad-based molecular profiling and biomarker assessment prior to therapy initiation for all patients with non-squamous NSCLC, when clinically feasible. For NSCLC, NCCN currently defines broad molecular profiling as "molecular testing that identifies all of the classic actionable biomarkers identified in the algorithm [i.e., ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, METex14skipping, NTRKJ/2/3, RET, ROSI] in either a single assay or a combination of a limited number of assays, and optimally also identifies emerging biomarkers (e.g., high-level MET amplifications and FGFR alterations)."

NCCN would like to clarify that the NCCN Guidelines for NSCLC recommend broad-based molecular profiling and biomarker assessment prior to therapy initiation for all patients with advanced or metastatic non-squamous NSCLC, when clinically feasible. In addition, the guidelines recommend that molecular testing via broad molecular profiling also be considered in patients with advanced or metastatic squamous NSCLC. For non-metastatic NSCLC, the NCCN Guidelines for NSCLC recommend testing for EGFR mutations in patients with stage IB-IIIC disease and ALK rearrangements in patients with stage IB-IIIB disease. NCCN respectfully requests that the LCD language be updated to reflect the guidelines to ensure alignment with current evidence-based recommendations.

Additionally, within the Summary of Evidence section, MolDX also states:

"In patients with advanced colorectal cancer (CRC), first-line treatment includes the use of targeted therapies informed by AODs, some of the most common being in the BRAF, KRAS, and EGFR NRAS genes. "

While MolDX cites NCCN as a source for this statement, the NCCN Guidelines for Colon Cancer identify the most common clinically relevant biomarkers in advanced CRC as BRAF, KRAS, and NRAS genes, in addition to MSI/MMR status. NCCN requests that the LCD language be revised to accurately reflect the guidelines cited.

Bibliography

NCCN would like to further note that outdated versions of the guidelines are cited within this LCD. As previously mentioned, the NCCN Guidelines are updated on a continual basis, with a minimum of one update annually, though more frequent updates commonly occur as science evolves. Because the field of biomarker testing in oncology continues to evolve rapidly, NCCN encourages MolDX to also consider referencing the NCCN Biomarker Compendium, which provides the most current information on biomarkers with clinical utility for various cancer types as determined by the Guideline panels. To further support the use of up-to-date information, the latest versions of the NCCN Guidelines and Compendia can always be found online, free of charge, at NCCN.org.

NCCN appreciates the opportunity to comment on the Palmetto GBA Proposed LCD MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer. NCCN thanks MolDX for its use of NCCN content and commitment to ensuring access to evidence-based care. NCCN is happy to serve as a resource and looks forward to working together to ensure Medicare beneficiary access to optimal cancer care.

References were provided for review.

Sincerely,

Crystal S. Denlinger, MD, FACP Chief Executive Officer

National Comprehensive Cancer Network

Thank you for your comment and support of this LCD. Please see our Responses above. Additionally -

We have updated the LCD language (and corresponding citations) to reflect the most current NCCN recommendations.

The following comment was submitted to CGS, Noridian, and WPS:

Thank you for the opportunity to provide comments on draft LCD - MolDX: Non- Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer. This policy, when finalized, will provide critical testing for patients diagnosed with cancer.

About Biocartis

Biocartis is an innovative molecular diagnostics company committed to helping cancer patients worldwide access the right treatment faster. With our proprietary Idylla™ Platform, we deliver accurate in-house molecular biomarker results using a simple sample-to-answer approach that does not require specialized personnel or laboratory facilities in only 3 hours. This enables healthcare professionals to make timely, informed decisions that guide personalized therapy. Our expanding portfolio of diagnostic tests and research assays addresses key unmet clinical needs across multiple cancers, including lung, skin, thyroid, colorectal, endometrial, blood, brain, and breast cancer.

Recommendations

We believe this draft LCD is critical to providing the best patient care. Non-NGS molecular biomarker panels can provide results much faster than Next Generation Sequencing panels allowing for physicians to have the critical information needed for treatment determinations. This gives patients the ability to be started on the appropriate treatment sooner as well as decreases the chance that the patient’s performance status deteriorates past the point where treatment can be given. It is our belief that non-NGS molecular biomarker tests and NGS complement each other. The non-NGS molecular biomarker tests allow for fast critical results while NGS provides more comprehensive results at the cost of longer turn-around-times. Based on the synergies between non-NGS molecular biomarker tests and NGS we make the following recommendations for the LCD.

Recommendation A: Removal of “non-duplicative” from Criteria #3

We understand the need to ensure that unnecessary, duplicative, testing is not done to preserve Medicare resources. However, the inclusion of the same genes and genomic positions is not duplicative as the NGS panel could detect low prevalence and rare

mutations of the genes and genomic positions. As a result, we request that the word “non- duplicative” be removed from criteria 3. This will also allow for laboratory and test consistency as labs have validated the NGS panel potentially inclusive of the genes and genomic positions. Some of the NGS panels are FDA cleared/approved, and the removing of the duplicative genes and genomic positions would be considered off-label and may not be possible. When the removal of the genes and genomic positions is possible, it could require additional validation. Without the removal of this criterion, it is possible that labs will see the need to remove the duplicate genes and genomic positions as too problematic. As a result, they could continue to solely use NGS to ensure reimbursement of the NGS panel thus preventing the adoption of non-NGS molecular biomarker tests that can provide faster, meaningful results to Medicare patients.

Recommendation B: Removal of Criteria #4

Criteria #4 in the draft LCD states “The test accurately detects the most common genes and genomic positions required for the identification of clinically relevant FDA-approved therapies with a companion diagnostic biomarker for the given cancer type.” By removing this criterion, it allows for the LCD to potentially provide coverage of critical biomarker tests that are diagnostic or prognostic but may not currently be associated with a companion diagnostic. In particular, non-NGS molecular biomarker tests are used to appropriately classify patients into molecularly defined sub-groups to determine the best treatment pathways, but these biomarkers are not always linked to a specific treatment. An example would be for endometrial cancer where guidelines recommend testing for POLE mutations, but this biomarker does not currently have an associated companion treatment although guidelines recommend treatment with immunotherapy. To ensure Medicare patients have access to novel care without delay, non-NGS molecular biomarker tests should not be limited to biomarkers with an associated companion treatment but rather should be able to have coverage for the same markers that physicians would find relevant in an NGS panel. We feel that the removal of this criterion maintains the proper use of biomarker tests as Criteria #2 c. addresses the need for the test to “… identify known, common, and necessary predictive biomarkers…” which ensures that the biomarker tests are being used in scientifically proven areas. Additionally, to ensure the validity of the relevance of the biomarkers in the test, the LCD has criteria #8 stating “Clinical validity (CV) of any analytes or profiles must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population with demonstrated reproducibility across clinical study cohorts”. If it is meaningful, criteria #8 could be consolidated in criteria #2c to address any concern of the biomarkers being scientifically validated for the intended use.

Recommendation C: Consolidation of Performance Criteria with deletion of Criterion #5 We appreciate the attention to details in the draft LCD. As a result, the performance criteria are addressed in many of the criteria throughout the LCD. We recommend consolidating criteria #6 and #9. These criteria both address the needed performance of the non-NGS molecular biomarker test but by different comparator methods. The current reading of the LCD could be interpreted that the non-NGS molecular biomarker test needs to have performance data against both NGS and a similar methodology. To prevent duplication of performance needs and prevent confusion, we suggest when combining these criteria that an “Or” be added to clarify that the test does not need multiple validation methods to be covered under the LCD. Additionally, the requirement of the Technical Assessment ensures that the validation of the test was done with the necessary rigor to demonstrate the analytical and clinical validity of the test. We also request the deletion of Criteria #5 as a part of this recommendation as it states, “The test has been validated in the intended-use population and with the intended-use sample types.” This is already addressed in Criteria #9 and will be addressed as apart of the Technical Assessment.

Additional Comments/Questions

We appreciate the need for the MolDX Technical Assessment (TA) to ensure the Analytical and Clinical Validity of the test be provided. Does MolDX intend to require a MolDX TA if the test has been FDA cleared/approved? We understand the desire for the Z-code but want to ensure no additional burden be placed on the lab when the test has been FDA cleared/approved demonstrating the performance.

Thank you for the opportunity to provide comments on MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer.

Table provided for review.

Sincerely,

Roger Moody

Chief Executive Officer Biocartis

1. Michael Korn, MD

Chief Medical and Scientific Officer Biocartis

Thank you for your comment and support of this LCD. Please see our Responses above. Additionally -

• It is expected that subsequent NGS testing, performed in accordance with the LCD, will include some of the same genes previously interrogated by a non-NGS panel. However, it is also expected that any NGS panel run after a prior negative non-NGS panel WILL include additional necessary genes and genomic positions beyond those found on the non-NGS panel.
• The LCD does not differentiate tests on the basis of FDA approval. All tests within scope of the LCD are expected to satisfy the criteria for coverage.

The following comment was submitted to WPS:

Thank you for the opportunity to comment on — MolDX: Non-Next Generation Sequencing Targeted Molecular Panel Tests for Predictive Testing in Cancer (posted September 25, 2025). I support the policy’s intent to clarify appropriate use of non-NGS methods when rapid, targeted results can guide care and when reflex to NGS remains available for broader profiling.

Recommendation on placement

Please consider inserting the following paragraph in the “Summary of Evidence” section immediately after the paragraph that begins “For some tumor types and populations, the most common mutations can be accurately detected by these advanced non-NGS methods…” (near the end of the Summary of Evidence). This location naturally follows the discussion of rapid TAT, tissue constraints, and reflex-to-NGS pathways and provides a concrete, evidence-based example consistent with the LCD’s purpose.

Proposed text for insertion (Summary of Evidence):

An illustrative example of appropriate non-NGS testing is serial plasma monitoring for emergent ESR1 mutations in ER-positive/HER2-negative metastatic breast cancer receiving first-line aromatase inhibitor (AI) plus CDK4/6 inhibitor. ESR1 hotspot mutations (e.g., Y537S, D538G) are a well-established mechanism of acquired AI resistance and can be sensitively detected in circulating tumor DNA using quantitative PCR (qPCR) or digital PCR (dPCR) with rapid turnaround suitable for repeated, cost-effective, longitudinal assessment. In the phase 3 PADA-1 trial, ddPCR-based detection of rising ESR1 mutations triggered an early endocrine switch (AI→fulvestrant) with continued CDK4/6 inhibition and significantly improved progression-free survival (PFS) versus continuing AI until radiographic progression. More recently, the phase 3 SERENA-6 study operationalized ctDNA ESR1 monitoring every 2–3 months and demonstrated that switching to camizestrant upon detection of an emergent ESR1 mutation prolonged PFS relative to continuing AI plus CDK4/6 inhibitor in the absence of radiologic progression. Although SERENA-6 used a ctDNA assay that can be performed by NGS, the clinical utility hinges on prompt identification of known ESR1 hotspots during ongoing therapy—an application for which validated non-NGS methods (e.g., PCR panels targeting ESR1 hotspots) are analytically suitable, operationally efficient, and cost-conserving in a repeated-testing paradigm. Reflex to NGS remains appropriate for broader genomic profiling when clinically indicated (e.g., ESR1-negative results or at progression).

Why this strengthens the Summary of Evidence

• It grounds the policy’s conceptual framework (rapid, focused results; reflex to NGS as needed) in a well-studied, practice-shaping use case with randomized phase 3 data (PADA-1, SERENA-6).
• It highlights a scenario where testing is repeated over time, making non- NGS targeted assays particularly appropriate from a turnaround and resource-utilization standpoint, consistent with the LCD’s rationale.
• It preserves policy neutrality by emphasizing that NGS remains essential when broader profiling is required (negative/atypical results, progression), aligning with the LCD’s reflex-to-NGS construct.

Additional recommended clarification

The clinical utility for ESR1 monitoring is documented at a testing frequency of every 2-3 months per the SERENA-6 trial. The current draft of DL40278 states "The patient has not been previously tested by a molecular panel test for the same cancer indication for the same genetic content.” in the Criteria for Coverage section. It is my understanding that repeat, single-gene ESR1 testing on the same genetic content would remain eligible for coverage as the prior ESR1 testing was not a molecular panel. The recommended clarification is to explicitly state ‘repeat single gene testing is covered on the same genetic content, if clinical utility is well documented’ in the Criteria for Coverage section.

Thank you for considering this addition. I believe it will make the Summary of Evidence more robust by anchoring the non-NGS framework in a high-quality, tumor-specific example that is timely, practice-relevant, and consistent with reflex-to-NGS principles.

References were provided for review.

Sincerely,

Jordan Laser, MD

Sr. Director, Clinical and Medical Affairs

Diagnostics and Spatial Biology Segment

Bio-techne

Thank you for your comment and support of this LCD. Please see our Responses above. Additionally -

• We have not inserted the paradigm of serial single-gene testing such as ESR1. Testing for hotspots in a single gene is not within scope of this LCD, which pertains to non-NGS panel testing. Please also refer to A59685, MolDX: Defining panel services in MolDX.

The following comment was submitted to CGS and WPS:

On behalf of the American Academy of Dermatology Association (AADA) and the Dermatologic Medicare Contractor Advisory Committee (DermCAC), thank you for the opportunity to comment on the MolDX proposed LCD for Non-Next Generation Sequencing (NGS) Targeted Molecular Panel Tests for Predictive Testing in Cancer and its accompanying draft billing and coding article. Overall, as we address in our comments below, we believe revisions to the proposed LCD are needed to ensure that physicians serving in consultative roles – as dermatologists routinely do – can order Non-NGS Targeted Molecular Panel Tests for Predictive Testing in Cancer.

The AADA is the leading society in dermatological care, representing more than 17,500 dermatologists nationwide. The AADA is committed to excellence in the medical and surgical treatment of skin disease; advocating for high standards in clinical practice, education, and research in dermatology and dermatopathology; and driving continuous improvement in patient care and outcomes while reducing the burden of skin disease. The DermCAC is a national coalition of dermatologists selected by their state dermatology societies to represent board-certified dermatologists in your carrier region. The DermCAC advocates for policies that prioritize patient well-being.

The AADA and DermCAC are concerned that the draft LCD, as written, is silent on which clinicians may order non-NGS targeted molecular panel tests for predictive cancer testing, which may leave the policy open to interpretation in a way that could restrict some clinicians — such as consulting physicians — from ordering these tests when clinically appropriate. We do not believe such an interpretation would be consistent with regulations at 42 CFR § 410.32 (as referenced in the draft LCD), which state that diagnostic tests must be ordered by the physician treating the beneficiary — defined as the “physician who furnishes a consultation [emphasis added] or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary’s specific medical problem.”

We believe lack of clarity regarding consulting physicians’ ability to order these tests could create unnecessary barriers to care, leading to delayed diagnosis and/or treatment. While dermatologists regularly manage patients’ overall dermatologic cancer treatment, they often serve in consulting roles as well. For example, a dermatologist diagnoses cutaneous melanoma metastasis. BRAF mutational analysis is ordered both to counsel the patient on treatment options and to expedite treatment once the patient is evaluated by hematology/oncology. Even in consultative cases like this, non-NGS molecular panel tests may provide additional diagnostic, prognostic, or predictive insight to help inform treatment decisions or timely and appropriate referrals as part of coordinated patient care. For such consulting physicians, who have relevant expertise and a strong understanding of the methodology and clinical utility of non-NGS molecular tests, it is important that they remain able to order such tests when the results may assist in diagnosis or guide treatment planning.

The AADA and DermCAC support policies that promote effective care coordination — particularly those that ensure specialists, including dermatologists, can meaningfully contribute to diagnosis and treatment decisions within physician-led, multi-specialty care teams. We have consistently emphasized the importance of ensuring that policies governing molecular diagnostic services do not limit test ordering to physicians formally designated as the treating clinician.

To avoid restricting the appropriate clinical use of non-NGS molecular panel testing and preserve patient access, we urge MolDX to include language clarifying that ordering physicians may include consulting physicians who are coordinating care with the treating clinician, in addition to physicians who are treating or managing the patient’s condition. This would help ensure that specialists and consultative physicians are not restricted from ordering non-NGS molecular panel testing when medically necessary and appropriate.

The AADA and DermCAC appreciate the opportunity to provide feedback on the proposed MolDX LCD and draft billing and coding article on non-NGS molecular panel tests for predictive cancer testing. Thank you for your consideration of these comments. On behalf of dermatologists in the WPS region and nationwide, the AADA and DermCAC remain committed to ensuring patients have access to high-quality, medically necessary dermatologic care. We value continued collaboration with Medicare Administrative Contractors on all policies impacting the specialty.

Sincerely,

Susan C. Taylor, MD, FAAD

President, American Academy of Dermatology / Association

Howard Wooding Rogers, MD, PhD, FAAD

Chair, Dermatologic Medicare Contractor Advisory Committee

Thank you for your comment and support of this LCD. Please see our Responses above. Additionally -

• We have not made any further statements regarding the type of physician who can order such tests and disagree that this would restrict patient access to relevant services.

The following comment was submitted to WPS:

I appreciate the opportunity to comment on the MolDx proposed LCD.

Background: May Policy Documents

For labs in MolDX jurisdictions, cancer gene panel testing panel testing in tumors involves many guidances at both NCD and LCD levels. There are multiple billing articles, multiple tumor testing policies (e.g. tissue CGP and LBx CGP.) There is also NCD 90.2, which guarantees coverage of both tissue and LBx FDA-approved tests regardless of panel size.

MolDx local policies and articles include:

• LCD covers next-generation sequencing in solid tumors.

• LCD covers plasma-based genomic profiling in solid tumors.
• LCD is supplemented by article, billing NGS in solid tumors, by article billing for targeted and comprehensive genomic profile testing, and defining panel services.

Areas for Clarification of Draft LCD (1,2,3)

1. Scope of Draft LCD – Tissue vs Liquid Biopsy Settings
2. It is clear that Draft LCD only addresses non-NGS assays.
3. It is not clear whether the policy applies to both tissue-based and plasma-based (LBx) tests.
4. For instance, would a ddPCR liquid biopsy test fall under the existing LBx LCD, or the non-NGS LCD, or both? Clarification on jurisdiction between the several LCDs would be helpful.
5. Define QNS, When LBx Testing is Available
6. MolDx currently covers plasma (LBx) testing under (1) NCD 90.2 for FDA-approved assays and under (2) the MolDx liquid biopsy LCD for LDTs.
7. This proposed LCD covers non-NGS testing when tissue is quantity-not-sufficient (QNS) for NGS.
8. However, in current practice, it is difficult to envision a patient scenario where LBx CGP is not available as an alternative. LBx CGP is specifically covered by MolDx when tissue is QNS.
9. Clarification is requested on how the QNS provision applies when liquid biopsy testing is rapid, available, and already covered under other policies.
10. Interpretation of Sequential Testing Language
11. The LCD states that if a patient has had non-NGS testing with a negative result, an NGS test may follow.
12. However, some payers (including Medicare Advantage plans) may interpret this to mean that a patient with a positive non-NGS result would not be eligible for subsequent NGS testing, even though MolDx has not stated this explicitly.
13. In many clinical scenarios, even when a rapid non-NGS test identifies one actionable alteration, broader NGS CGP may still be medically necessary (e.g., to assess TMB, MSI, BRCA, ESR1, or other biomarkers).
14. To prevent misinterpretation, consider clarifying that a positive non-NGS result does not preclude NGS-based CGP when additional genomic information could inform management.

Clarity Remarks (4,5)

4. Coverage Criterion 2 – Readability and Logical Clarity
5. This criterion contains three separate conditions, stating that only one must be met. This implies that any two of these conditions can be “failed” but the test is still covered.
6. Condition (a) concerns the individual patient and the feasibility of biopsy for that patient.
7. Condition (b) concerns national guideline recommendations for a specific cancer type.
8. Condition (c) concerns the non-NGS test itself and includes two sub-parts with different topics.
9. MolDx may wish to review this section for readability—particularly to avoid double negatives and to make the logic of “at least one of the following” easier to follow.
10. Clarification is requested on whether MolDx truly intends that a test could be covered even when two of the three conditions are not met. For example, you will cover non-NGS tests when tissue is QNS (#1 passes) and also when tissue is sufficient (#1 fails), but a guideline passes condition 2 or the test itself passes condition 3.
11. Criterion 2, Condition (c) – Two Distinct Rules in One Statement
12. Criterion 2(c) currently combines two separate rules into one coverage condition. The result could be TT, TF, FT, FF.
13. It may improve clarity to separate these into two distinct criteria. The first sentence applies to patients who have not yet undergone molecular testing—which may be self-evident. The second sentence refers to coverage for further testing (e.g., NGS) after prior non-NGS testing that had negative results, which raises different considerations and interacts with other LCDs.

Thank you for the chance to comment on this proposed LCD.

Sincerely,

Bruce Quinn MD PhD
Principal

Bruce Quinn Associates LLC

Thank you for your comment and support of this LCD. Please see our Responses above. Additionally -

• It is correct that MolDX has published numerous LCDs addressing genomic profiling in cancer. The current LCD addresses non-NGS assays, specifically for Targeted Molecular Panel Tests for Targeted Therapy in Cancer, but is not specific to tissue vs. plasma-based tests. It also does not conflict with the other national or MolDX policies. For example, LCD L39230, MolDX: Plasma-Based Genomic Profiling in Solid Tumors, is specific to NGS tests.
• NGS-based testing after a positive non-NGS result for an actionable biomarker is considered duplicative testing when performed for the same cancer indication and genetic content. IF additional genomic information beyond what is available on the non-NGS panel will inform management and this is known prior to testing, then a non-NGS panel should NOT be performed. Please also see the associated Billing Article for billing instructions related to denials and appeals.

The following comment was submitted to WPS:

AstraZeneca appreciates the opportunity to submit comments on the above-captioned proposed local coverage determination (LCD) in support of coverage policy for appropriate use of non-NGS testing methods to detect the ESR1 (estrogen receptor 1) mutations (ESR1m).

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas—Oncology, Cardiovascular, Renal & Metabolism (CVRM) and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

Across AstraZeneca’s therapeutic areas, and especially in Oncology, AstraZeneca is working to advance precision medicine by pinpointing the unique genomic drivers of disease and targeting them with tailored therapies to improve patient outcomes. Recent results from the SERENA-6 study¹ demonstrate this commitment as the first pivotal trial to demonstrate the clinical value of monitoring circulating tumor DNA to detect and treat emerging resistance during 1st-line therapy ahead of disease progression in breast cancer.

The novel trial design used ctDNA monitoring to detect emergent ESR1m, helping identify patients with early signs of endocrine resistance. Following identification of emergent ESR1m, the endocrine therapy was switched to camizestrant, a next-generation selective estrogen-receptor (ER) degrader and complete ER antagonist, from ongoing treatment with an aromatase inhibitor (AI), while continuing combination with the same cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i), ultimately resulting in prolonged progression free survival (PFS) and delayed deterioration in patient-reported global health status and quality of life (QoL).

Given the criticality of timely identification of emergent ESR1 mutations to guide the evolving therapeutic approach, analytically validated non-NGS testing methods may also be appropriate, providing the option for rapid result delivery and identification of cancer genomic changes within a monitoring framework, thus providing the opportunity for therapeutic intervention ahead of clinical progression.

AstraZeneca recommends coverage of repeat testing, including non-NGS testing, to support ESR1m monitoring.

The current coverage criteria of the draft LCD state that to be eligible for coverage, “The patient has not been previously tested by a molecular panel test for the same cancer indication for the same genetic content.”

AstraZeneca recommends the LCD allow coverage of repeat testing when the LCD’s other criteria are satisfied. Given that mutations may evolve during treatment for certain cancers, this clarification will reflect that patient-specific circumstances (and history) for testing may vary. At a minimum, AstraZeneca recommends coverage of repeat ESR1 testing given the emerging therapeutic evidence.

AstraZeneca appreciates the opportunity to comment on the proposed LCD’s efforts to support coverage of non-NGS testing methods.

Sincerely,

Sarah C. Arbes

Head of Federal Affairs and Policy

Thank you for your comment and support of this LCD. Please see our Responses above.

The following comment was submitted to Palmetto GBA:

LUNGevity Foundation appreciates the chance to submit remarks on Draft LCD, as MolDx considers revisions for a final version. We recognize that our remarks fall outside the autumn comment period, and we will keep them brief and general.

We are supportive of the overall intention of the LCD, which will clarify that rapid non-NGS tests are sometimes medically necessary to ensure rapid access to important targeted treatments. At the same time, it is a standard of care to provide comprehensive genomic profiling, considering the full spectrum of mutations (single nucleotide, small indel, copy number, and rearrangements) as well as less-common genes that are critical routes to therapy (e.g. Ros-1). Many patients also benefit from larger panels that include tumor mutational burden, MSI (Microsatellite Instability) and HRD (Homologous Recombination Deficiency), and larger-scale sequencing that allows creation of bespoke panels for minimal residual disease detection.

We urge MolDx to be sure that any final wording is clear about the complementary, non-overlapping roles of very rapid limited testing and comprehensive testing, especially in lung cancer patients. Clarity is even more important because MolDx LCDs may be templates for LCDs in non-MolDx MACs, and must be interpreted by Medicare Advantage plans as well as commercial and Medicaid plans in the states with state biomarker laws based on Medicare coverage.

Thank you for the ongoing hard work of MolDx staff to ensure prompt and medically necessary access to molecular testing.

Nikki Martin
Senior Director, Precision Medicine Initiatives

Thank you for your comment and support of this LCD. Please see our Responses above.