LCD Reference Article Response To Comments Article

Response to Comments: MolDX: Minimal Residual Disease Testing for Cancer

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A58953
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Response to Comments: MolDX: Minimal Residual Disease Testing for Cancer
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Response to Comments
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01/02/2022
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The comment period for the MolDX: Minimal Residual Disease Testing for Cancer DL38814 Local Coverage Determination (LCD) began on 10/08/2020 and ended on 11/22/2020. The notice period for L38814 begins on 11/18/2021 and will become effective on 01/02/2022.

The comments below were received from the provider community.

Response To Comments

Number Comment Response
1

The following comment was submitted to Palmetto GBA, CGS, WPS and Noridian and was received from multiple stakeholders:

Define and clarify the service to include how this policy relates to NCD 90.2, what the protocol is for the process of monitoring a disease state over time using MRD testing at the local coverage level, and clarify whether this LCD only applies to NGS-based testing or if it will also cover a single gene assays used for monitoring.

A. Defining a MRD test –

As stated in the policy, MRD testing can be used to:

  • diagnose cancer progression, recurrence, or relapse before there is clinical, biological, or radiographical evidence of progression, recurrence or relapse
  • detect tumor response to therapy by measuring the proportional changes in the amount of available tumor DNA

First, MRD tests are diagnostic tests with various intended uses, including therapeutic monitoring. “Diagnostic testing has become indispensable for diagnosing and monitoring disease, for providing prognoses and for predicting treatment responses.” (Bulletin of the World Health Organization 2017;95:639-645). Diagnostic tests are not considered as distinct from ‘monitoring tests.’ Diagnostic tests are covered Medicare benefits.

Second, a MRD test, as defined in this policy, is a service that may include multiple components and/or multiple timepoints (i.e., serial assays). Testing schedules are set based on the validity established for the individual test comprising the service. Each component and timepoint of the service must be reasonable and necessary and adhere to the criteria set forth in this policy.

Finally, repeat testing by NGS using the same test for the same cancer genetic content is not allowed by NCD 90.2. NCD 90.2 allows for repeat NGS testing when there is clinical evidence of a priori change in genetic content, such as the development of resistance to a targeted therapy. Though MRD testing also involves the assessment of (quantitative or qualitative) changes in genetic content that may indicate progression, recurrence, or relapse, the goal of MRD testing is to precede clinical evidence of such events, so as to guide and hasten changes in management. Therefore, MolDX maintains that MRD testing is not testing for new genetic content, as per the intent of NCD 90.2.

B. Clarifying the serial testing process/ordering and billing for monitoring a disease state over time

The policy and Billing and Coding Article have been revised for clarity.

The final paragraph of the Coverage Indications has been revised as follows:

MRD testing often requires two types of assays to be performed as part of the service. First, a sample is taken from tumor diagnostic material to establish a baseline (solid and/or liquid) tumor signature as defined by the test methodology. This is followed by a series of assays run on a minimally invasive specimen (i.e., liquid biopsy or bone marrow aspirate) to detect the presence or recurrence of tumor based on the measured biomarkers, expression, or other analytes over various timepoints. Other approaches are also acceptable, based on the validity established for the individual test comprising the service. This series of assays comprises a single test when the patient is known to have cancer.

Therefore, the policy outlines how MRD testing is typically performed and acknowledges that other approaches to testing are acceptable. Additionally, tissue-based baseline testing would not be applicable to all cancers. Finally, as already stated, testing schedules are set based on the validity established for the individual test comprising the service. Each component and timepoint of the service must be reasonable and necessary and adhere to the criteria set forth in this policy.

Additional clarification is provided in the related Billing & Coding Article. For patients with cancer, tests (exclusive of standard-of-care single-gene PCR tests) should be billed as 1 unit of service (UOS) at the start of the episode of testing, regardless of the number of assay timepoints or components involved. This is based on the demonstration of the clinical validity and clinical utility of the service, and in accordance with the requirements established in the policy.

Further, for patients without cancer (as defined in the policy), a second kind of test may exist wherein a single timepoint may constitute a single test (i.e., 1 UOS for a given date of service). Testing may not be performed more than once in a month; the testing schedule is set based on the validity established of the individual test for the given indication.

For patients with or without cancer (as defined in the policy), established standard-of-care MRD tests using single-gene PCR (i.e., BCR-ABL1) may be billed on an individual basis according to testing schedules outlined in national (i.e., NCCN) or society guidelines, with 1 UOS for each date of service.

C. Defining and expanding the specimen types and technologies covered by the policy

The Coverage Indications section has been revised to clarify the specimen types and technologies covered by this policy.

The section now begins with:

This Medicare contractor will provide limited coverage for minimally invasive molecular (DNA and RNA) tests that detect minimal residual disease (MRD) in patients with a personal history of cancer….

Further, Coverage Indication #1 states “IF NGS methodology is used…” which suggests that other methodologies are acceptable, so long as the test fulfills all criteria outlined in the policy.

To further clarify the specimen types and technologies covered by this policy, the Coverage Indications also state:

MRD testing often requires two types of assays to be performed as part of the service. First, a sample is taken from tumor diagnostic material to establish a baseline (solid and/or liquid) tumor signature as defined by the test methodology. This is followed by a series of assays run on a minimally invasive specimen (i.e., liquid biopsy or bone marrow aspirate) to detect the presence or recurrence of tumor based on the measured biomarkers, expression, or other analytes over various timepoints. Other approaches are also acceptable, based on the validity established for the individual test comprising the service. This series of assays comprises a single test when the patient is known to have cancer…..

For patients with or without cancer (as defined in the policy), established standard-of-care MRD tests using single-gene PCR (i.e., BCR-ABL1) are covered under this policy according to testing schedules outlined in national (i.e., NCCN) or society guidelines.

MRD testing in accordance with this policy can be performed using PCR and/or sequencing-based technologies and is not restricted to a single type of biological material or defined number of genes.

2

The following comment was submitted to Palmetto GBA, CGS, WPS and Noridian and was received from multiple stakeholders:

Request inclusion of additional Hematologic malignancies and associated MRD tests.

We recognize that MRD testing is relevant in additional hematologic malignancies beyond ALL, CLL, and multiple myeloma. We agree that MRD testing for these additional hematologic malignancies is guided by evidence and supported by nationally recognized guidelines and is therefore appropriate for inclusion in this policy. Therefore, the policy now contains a more expansive discussion and coverage for MRD testing in additional lymphoid and myeloid malignancies. This is also reflected in the codes included in the Billing and Coding Article.

Further, we recognize and have addressed the issue of MRD testing from acellular as well as cellular specimens in hematologic malignancies. As now written in the policy, MRD testing in accordance with this policy can be performed using PCR and/or sequencing-based technologies and is not restricted to a single type of biological material or defined number of genes.

To address the comments received, the discussion of MRD techniques used in hematologic malignancies in the current policy has also been expanded to better reflect differences between different cancer types and different tests.

Finally, it is important to note that there is an existing policy regarding NGS testing in myeloid malignancies: MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies. That policy’s focus is not MRD testing. Moreover, that policy’s scopeis specific for MYELOID malignancies and suspected malignancies, and is exclusive of solid tumor testing, circulating tumor DNA (ctDNA) testing, and other cancer-related uses of NGS, such as in germline testing.”

3

The following comment was submitted to Palmetto GBA, CGS, WPS and Noridian and was received from multiple stakeholders:

Define and clarify the use of this test in relation to other tests (i.e., perceived preclusion of concurrent radiology) and specific therapies.

A. Relation of MRD test to other tests

We agree that (a) not all cancers share the same monitoring guidelines, (b) MRD tests may be required in conjunction with radiographic tests for non-redundant clinical information (i.e., lytic lesions in multiple myeloma; the presence and extent of disease and invasion; organ and lymph node size), depending on the cancer type, timeframe for monitoring, and established guidelines, and (c) comparability of sensitivity and specificity is best addressed in relation to the information provided by a given test modality. Therefore, we have modified the language of Coverage Criteria #4 and #5 as follows:

Coverage Criterion #4: The test is demonstrated to identify molecular recurrence or progression before there is clinical, biological, or radiographical evidence of recurrence or progression AND demonstrates sensitivity and specificity of subsequent recurrence or progression comparable with or superior to radiographical or other evidence (as per the standard-of- care for monitoring a given cancer type) of recurrence or progression

Coverage Criterion #5: To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests intended to provide the same or similar information, unless they either (a) are required to follow-up or confirm the findings of this test or (b) are medically required for further assessment and management of the patient.

'Medical Acceptability’ and 'established’ in the context of this policy refer to known and well-accepted standard-of-care practices based on national or society guidelines.

B. Relation of MRD test to specific therapies

We agree that the requirement for the test to have published clinical validity for ‘the explicit therapy indicated’ could be overly restrictive and impractical, given the number and diversity of explicit therapies approved for various cancer types. However, the fact that multiple drugs may belong to the same therapeutic class should not presume they are equivalent in terms of their applicability to MRD testing. As such, we have clarified coverage Criterion #6 such that it now reads:

If the test is to be used for monitoring a specific therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit management or therapy indication (allowing for the use of different drugs within the same therapeutic class, so long as they are considered ‘equivalent and interchangeable’ for the purpose of MRD testing, as determined by national or society guidelines)

Finally, this statement begins with 'IF’; therefore, the MRD test need not be used for monitoring a specific therapeutic response. The policy as-written therefore allows for a MRD test that is independent of a specific therapy or intervention.

4

The following comment was submitted to Palmetto GBA, CGS, WPS and Noridian and was received from multiple stakeholders:

Request clarification regarding standards used to assess and compare tests.

It is the expectation of MolDX that a MRD test is ordered by the treating physician and is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

The publication of test results in the literature, though a requirement of the policy, often cannot stand alone as proof of the technical and performance rigor of a test. Endorsement of a test by national or society guidelines may provide additional support in favor of a test’s clinical validity and utility. These are all considered by MolDX during evaluation of a test for coverage.

MolDX additionally performs rigorous and comprehensive Technical Assessment (TA)s which ensure that all required policy coverage criteria are met and that the appropriate clinical and scientific rigor have been applied during a test’s evaluation and performance. MolDX applies these standards to evaluate the analytical validity, clinical validity, and clinical utility of a test. Therefore, MolDX evaluates new MRD tests not just in terms of the explicit molecular content interrogated and the analytical performance characteristics of a test, but also within the context of the clinical questions the test is intended to address, as well as its ability to inform management. Further, comparisons between tests are appropriate when tests have the same intended uses in the same intended-use populations. It is therefore the expectation of MolDX that comparable tests in this regard also demonstrate similar technical performance characteristics. Though a head-to-head clinical trial comparing a new test to an established method for MRD testing may be one approach to evaluate comparability between tests, other approaches are acceptable so long as they employ appropriate clinical and scientific rigor.

Finally, elements required for a proper analytical validation and evaluation of technical test performance are widely known and are provided by CAP, CLIA, AMP, and other society guidelines. Therefore, a list of these elements individually does not belong in the policy.

We refer you to Coverage Criteria #7 - #10 in the revised policy.

Specifically, Coverage Criterion #9 states: The MRD test (unless it is a FDA-approved and established standard-of-care single-gene PCR) satisfactorily completes a technical assessment that will evaluate and confirm that the analytical validity, clinical validity, and clinical utility criteria set in this policy are met to establish the test as Reasonable and Necessary. Coverage Criterion #10 states: Tests utilizing a similar methodology or evaluating a similar molecular analyte to a test for which there is a generally accepted testing standard or for which existing coverage exists must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the same intended-use population.

5

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

The American Cancer Society Cancer Action Network (ACS CAN) appreciates the opportunity to submit comments on the proposed local coverage determination (LCD) for minimal residual disease testing for cancer (proposed LCD). ACS CAN is making cancer a top priority for public officials and candidates at the federal, state, and local levels. ACS CAN empowers advocates across the country to make their voices heard and influences evidence-based public policy change, as well as legislative and regulatory solutions that will reduce the cancer burden. As the American Cancer Society’s nonprofit, nonpartisan advocacy affiliate, ACS CAN is critical to the fight for a world without cancer.

ACS CAN supports the proposed LCD for minimal residual disease testing for cancer. The evidence base demonstrating the utility of diagnostic laboratory tests that analyze bodily fluids for circulating tumor DNA (ctDNA) biomarkers to detect minimal residual disease (MRD) has been growing and marks an important development in the diagnosis and treatment of cancer. Different testing techniques are used across both hematologic and solid cancers to assess and monitor MRD. These include flow cytometry, polymerase chain reaction, and next-generation sequencing (NGS) which encompasses a number of different sequencing techniques.

As indicated in clinical practice guidelines, such as the National Comprehensive Cancer Network’s (NCCN) Clinical Practice Guidelines in Oncology, the application of ctDNA tests to detect MRD can be a reliable indicator of cancer recurrence or progression. Monitoring for MRD in patients offers an approach that can potentially indicate that cancer is returning before clinical or radiographical signals would detect such a recurrence. Additionally, MRD detection can indicate response to therapy and help direct patients to alternative or additional therapies for their cancer.

While there have been coverage determinations in Medicare for ctDNA testing, they have primarily focused on non-small lung cancer and for treatment indications. ACS CAN is a pleased that this LCD provides coverage for ctDNA testing for monitoring indications across cancer types. Furthermore, we appreciate this foundational policy will allow future tests to be included in an ongoing basis based on satisfactorily completed technical assessments under the Molecular Diagnostic Services (MolDX) Program, to review and confirm a test’s analytical and clinical validity.

The proposed LCD supports ACS CAN’s view that coverage of biomarker testing should not be restricted to a single occurrence if the test is designed to monitor disease progression and therefore must be serially administered. Thank you for the opportunity to provide comments on this important issue for cancer patients.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

6

The following comment was submitted to CGS and Noridian:

Novartis Services, Inc. is submitting this letter on behalf of Novartis Pharmaceuticals Corporation referred herein as “Novartis.” We appreciate the opportunity to submit comments on the proposed Local Coverage Determination (LCD): Minimal Residual Disease Testing for Cancer.

Novartis provides healthcare solutions that address the evolving needs of patients and societies worldwide. Our broad portfolio of medicines includes treatments in the areas of ophthalmics; neuroscience; immunology, hepatology and dermatology; respiratory; cardiovascular, renal and metabolism; oncology, including targeted therapies, immuno-oncology, chimeric antigen receptor T cells (CAR-T) and radioligand therapy; and gene therapies. We are also a global leader in generic and biosimilar medicines, committed to playing a leading role in driving access to medicine worldwide.

At Novartis, we are united by a single purpose to reimagine medicine to improve and extend people’s lives. Through innovative science and technology, we address some of society’s most challenging healthcare issues. Every day we work to discover and develop breakthrough treatments and find new ways to deliver them to as many people as possible. Our vision is to be the most valued and trusted medicines company in the world.

We appreciate the opportunity to seek clarification and share comments regarding this proposed LCD. The draft LCD aims to apply to both solid tumors and to hematopoietic malignancies, but we believe the limits do not actually apply appropriately to both. The coverage guidance refers specifically to molecular circulating tumor DNA (ctDNA) tests. In the field of hematological malignancies, the biological specimens used for MRD testing are from bone marrow, peripheral blood mononuclear cells (PBMC) and from plasma.

We believe that MolDX should not restrict access to a single type of biological material and associated technology, which limit MRD-testing to only special cases and may result in excluding patients for not receiving the appropriate testing over the course of their treatment that could identify recurrence and/or progression of their cancer. The LCD should include clinically appropriate biological specimens to enable MRD-testing in all patients with a personal history of solid cancer and/or hematological cancer. Novartis proposes that the LCD adopt the following agnostic language: “This Medicare contractor will provide limited coverage for analytical tests that detect minimal residual disease (MRD) in patients with a personal history of cancer.”

We also have specific concerns regarding points 1 and 5 of the coverage limitations provided on page 3. Point 1 addresses specifically the NGS method for MRD testing. In the current field, MRD tests are not solely NGS-based. Other molecular methods based on Polymerase Chain Reaction (PCR) such as real-time or quantitative are also commonly used. Flow cytometry (FCM) is also a method used to detect minimum residual disease. The LCD should not restrict access to a single sequencing technology to detect MRD because in some instances, PCR and FCM are providing better sensitivity than NGS. Such restriction will exclude patients from receiving testing during the course of their treatment that could identify recurrence and/or progression of their cancer. Novartis recommends expanding the coverage guidance to the three most common methods used to detect minimal residual disease: FCM, NGS and PCR.

Point 5 of the coverage guidance specifies “sensitivity and specificity considerably more accurate than other established (non-MRD) forms of surveillance or monitoring”. Furthermore, coverage guidance points 6 to 8 strengthen the importance of the technical rigor of the MRD test yielding quality results. However, publication of test results in literature is not proof of the technical and performance rigor of the test. To achieve the technical and performance rigor for sensitivity, specificity, reproducibility, and validity deemed necessary to improve health outcomes for Medicare beneficiaries with cancer, a FDA cleared test or CLIA-test should be used. Novartis recommends adding to point 5 the following: “the MRD-test must be ordered by the treating physician and performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.”

Additionally, in the Summary of Evidence section, under the Examples of current uses for MRD in hematopoietic malignancies on page 7, Novartis recommends to include Chronic Myeloid Leukemia (CML) to the list of hematological malignancies where MRD is used to guide treatment decision. Novartis proposes the insertion of the following language shown in bold italics:

MRD use in certain hematological malignancies has been well established in the scientific literature and is used as a patient risk stratification tool and to guide treatment decisions. These include Chronic Myeloid Leukemia (CML) where BCR-ABL RNA PCR tests reliably detects the presence of leukemic cells at very low levels (1 tumor cell in 100,000 normal cells) in Tyrosine Kinase-treated patients. These include as well acute lymphoblastic leukemia (ALL), Multiple Myeloma (MM), and Chronic Lymphocytic Leukemia (CLL) where some MRD tests, such as clonoSEQ (Adaptive Biotechnologies) have demonstrated the ability to reliably detect and monitor tumor DNA from as little as 200-500ng DNA.

Thank you for considering our recommendations regarding the proposed LCD.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally -

PCR and sequencing-based technologies are included in this policy; however, flow cytometry (FC) is not. Flow cytometry is not a molecular (DNA or RNA) laboratory test and is therefore outside the scope of this policy.

Further, for select cancers and at select timepoints, if FC adds unique value beyond the information provided by the molecular MRD test (i.e., it is medically required for further assessment and management of the patient), then its performance is not precluded by the conditions of Coverage Criterion #5, which states:

To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests intended to provide the same or similar information, unless they either (a) are required to follow-up or confirm the findings of this test or (b) are medically required for further assessment and management of the patient.

7

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

The Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) write to provide joint comments on MolDX’s proposed coverage policy for Minimal Residual Disease Testing for Cancer. We appreciate the opportunity to review and provide joint comments as our organizations share the same perspective regarding this draft LCD.

The AMP is an international medical and professional association representing approximately 2,500 physicians, doctoral scientists, and medical technologists who perform or are involved with laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Membership includes professionals from the government, academic medicine, private and hospital-based clinical laboratories, and the in vitro diagnostics industry.

The CAP is the world’s largest organization of board-certified pathologists and the leading provider of laboratory accreditation and proficiency testing programs. The CAP serves patients, physicians, hospitals and healthcare systems worldwide, fostering and advocating excellence in the practice of pathology and laboratory medicine.

Together, we would like to thank you for proposing coverage of minimal residual disease testing (MRD) for cancer. We believe thoughtful consideration was given to this issue, and the resulting proposed LCD will positively impact patient care and other payers will be encouraged to follow with other less expensive testing for cancer. Further, we appreciate the addition of the following language about future revisions to the LCD as technology evolves:

This remains a rapidly evolving field, and we anticipate that new evidence may emerge either showing limitations of the clinical utility underlying MRD testing or additional strengths and new applications. Additionally, this coverage decision is based heavily on paradigm for care which was not developed for MRD testing. In summary, we anticipate future revisions to this coverage decision as the science and standard of care evolves, which may further limit or expand coverage for MRD testing.

AMP and CAP fully agree that this is a necessary addition to the proposed coverage policy.

Below and outlined in this comment letter are AMP and CAP’s recommendations for the draft LCD and we appreciate your consideration of our comments.

Coverage Indications, Limitations, and/or Medical Necessity

AMP and CAP wish to provide the following comments on specific coverage requirements included in the draft LCD:

If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD 90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content) or are not applicable (the patient does not have cancer as defined below)

MRD testing has two very important uses—to diagnose cancer recurrence before clinical or radiological evidence, and to monitor response to therapy. Monitoring response to therapy automatically involves testing more than once during the lifetime of a patient as it is repeated over the duration of the treatment. It is important to note that an initial diagnostic test may or may not be the same assay that is utilized to follow a patient over time, depending on the design of the test panel. If you are using the same NGS-based test for diagnosis and monitoring, there will be more than one of these tests performed during the patient’s lifetime.

AMP and CAP recognize that this proposed LCD needs to be designed within the parameters set forth in NCD 90.2, which provides contractors authority to cover NGS tests as a diagnostic laboratory test for patients with cancer in certain circumstances, and includes language which appears to place certain restrictions on repeat testing. AMP and CAP interpret the NCD language as serving to block duplicative NGS testing, while, at the same time allowing repeat testing for different and evolving genetic content (i.e., testing that is performed to monitor response to therapy). Thus, MRD testing using NGS-based methods for the use of monitoring a patient’s response to therapy is outside the scope of the NCD (i.e., monitoring is not a diagnostic test). Our organizations recommend adding language to the LCD making this distinction clear to eliminate any confusion. AMP and CAP offer to be a resource for further discussions on the flexibility of testing.

As drafted, the policy states the following:

MRD testing often requires two types of assays to be performed as part of the service. First, a sample is taken from tumor diagnostic material to establish a baseline tumor signature as defined by the test methodology. This is followed by a series assays run on blood to detect the presence or recurrence of tumor based on the measured biomarkers, expression, or other analytes over various timepoints. This series of assays comprises a single test when the patient is known to have cancer.

MolDX has designed an LCD that appears to allow for MRD testing by applying and then circumventing the repeat testing provision within NCD 90.2 by encompassing a series of assays as one service. AMP and CAP seek clarity on exactly how such processes will be set forth in clinical practice. We request that MolDX provide greater transparency about what the protocol is for the process of monitoring a disease state over time using MRD testing at the local coverage level (e.g., how ordering and billing are performed if “a series of assays comprises a single test” as described in the LCD).

We are concerned that this criterion will create a significant administrative burden for laboratories and is not necessary if the repeat testing provision within the NCD is appropriately applied to only repeat diagnostic testing using the same genetic content.

Furthermore, we request clarification on whether this LCD only applies to NGS-based testing or if it will also cover a single gene assays used for monitoring. As previously mentioned, there are different indications for testing – diagnosis and monitoring over time as with MRD. For example, in AML there is monitoring via key translocations [t(15;17), t(8;21), inv(16), and t(9;22)] as well as individual expression levels or mutations in WT1, NPM1, FLT3-ITD, RUNX1. Additionally, for AML it is well established to do single gene MRD for NPM1 mutations by qPCR (Ivey A et al, 2016; Dillon R et al, 2020; Kapp-Schwoerer S et al, 2020; Thol F et al, 2018). This field is and will continue to evolve rapidly and some tests may be practical to use every month or every other month as opposed to on a quarterly or one-time basis, and other tests might be more adequate to use just once to guide adjunctive therapy decisions.

The test is demonstrated to identify recurrence or progression with sensitivity and specificity that is considerably more accurate than other established (non-MRD) forms of surveillance or monitoring. To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests unless they are required to follow-up or confirm the findings of this test.

AMP and CAP request that MolDX define “medically acceptable” and/or provide clarification on who might determine whether something is considered “medically acceptable.”

MRD in Hematopoietic Malignancies

We recognize and appreciate that MolDX specifically mentions the following three disease states that are specifically mentioned in the National Comprehensive Cancer Network (NCCN) guidelines: acute lymphoblastic leukemia (ALL), Multiple Myeloma (MM), and Chronic Lymphocytic Leukemia (CLL). However, we request that MolDX consider including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) to the list of disease states. Molecular MRD testing for AML and MDS has been shown in multiple studies to be a strong and early predictor of relapse risk for patients treated with both conventional chemotherapy and stem cell transplant. The references listed in this letter below include research and evidence that demonstrates clinical utility of molecular MRD in AML and MDS in panel based NGS, single gene mutation assays, and translocation- based qPCR. Again, as uses for MRD testing grows, we offer AMP and CAP member expertise as a resource to MolDX to help ensure this LCD aligns with current evidence.

ICD-10 Coding

We request additional ICD-10 codes be added to the associated coverage article including, but not be limited to, the following:

  • C61 Malignant neoplasm of prostate
  • C82 Follicular lymphoma
  • C82.0 Follicular lymphoma grade I
  • C82.00 Follicular lymphoma grade I, unspecified site
  • C82.01 Follicular lymphoma grade I, lymph nodes of head, face, and neck
  • C82.02 Follicular lymphoma grade I, intrathoracic lymph nodes
  • C82.03 Follicular lymphoma grade I, intra-abdominal lymph nodes
  • C82.04 Follicular lymphoma grade I, lymph nodes of axilla and upper limb
  • C82.05 Follicular lymphoma grade I, lymph nodes of inguinal region and lower limb
  • C82.06 Follicular lymphoma grade I, intrapelvic lymph nodes
  • C82.07 Follicular lymphoma grade I, spleen
  • C82.08 Follicular lymphoma grade I, lymph nodes of multiple sites
  • C82.09 Follicular lymphoma grade I, extranodal and solid organ sites
  • C82.1 Follicular lymphoma grade II
  • C82.10 Follicular lymphoma grade II, unspecified site
  • C82.11 Follicular lymphoma grade II, lymph nodes of head, face, and neck
  • C82.12 Follicular lymphoma grade II, intrathoracic lymph nodes
  • C82.13 Follicular lymphoma grade II, intra-abdominal lymph nodes
  • C82.14 Follicular lymphoma grade II, lymph nodes of axilla and upper limb
  • C82.15 Follicular lymphoma grade II, lymph nodes of inguinal region and lower limb
  • C82.16 Follicular lymphoma grade II, intrapelvic lymph nodes
  • C82.17 Follicular lymphoma grade II, spleen
  • C82.18 Follicular lymphoma grade II, lymph nodes of multiple sites
  • C82.19 Follicular lymphoma grade II, extranodal and solid organ sites
  • C82.2 Follicular lymphoma grade III, unspecified
  • C82.20 Follicular lymphoma grade III, unspecified, unspecified site
  • C82.21 Follicular lymphoma grade III, unspecified, lymph nodes of head, face, and neck
  • C82.22 Follicular lymphoma grade III, unspecified, intrathoracic lymph nodes
  • C82.23 Follicular lymphoma grade III, unspecified, intra-abdominal lymph nodes
  • C82.24 Follicular lymphoma grade III, unspecified, lymph nodes of axilla and upper limb
  • C82.25 Follicular lymphoma grade III, unspecified, lymph nodes of inguinal region and lower limb
  • C82.26 Follicular lymphoma grade III, unspecified, intrapelvic lymph nodes
  • C82.27 Follicular lymphoma grade III, unspecified, spleen
  • C82.28 Follicular lymphoma grade III, unspecified, lymph nodes of multiple sites
  • C82.29 Follicular lymphoma grade III, unspecified, extranodal and solid organ sites
  • C82.3 Follicular lymphoma grade IIIa
  • C82.30 Follicular lymphoma grade IIIa, unspecified site
  • C82.31 Follicular lymphoma grade IIIa, lymph nodes of head, face, and neck
  • C82.32 Follicular lymphoma grade IIIa, intrathoracic lymph nodes
  • C82.33 Follicular lymphoma grade IIIa, intra-abdominal lymph nodes
  • C82.34 Follicular lymphoma grade IIIa, lymph nodes of axilla and upper limb
  • C82.35 Follicular lymphoma grade IIIa, lymph nodes of inguinal region and lower limb
  • C82.36 Follicular lymphoma grade IIIa, intrapelvic lymph nodes
  • C82.37 Follicular lymphoma grade IIIa, spleen
  • C82.38 Follicular lymphoma grade IIIa, lymph nodes of multiple sites
  • C82.39 Follicular lymphoma grade IIIa, extranodal and solid organ sites
  • C82.4 Follicular lymphoma grade IIIb
  • C82.40 Follicular lymphoma grade IIIb, unspecified site
  • C82.41 Follicular lymphoma grade IIIb, lymph nodes of head, face, and neck
  • C82.42 Follicular lymphoma grade IIIb, intrathoracic lymph nodes
  • C82.43 Follicular lymphoma grade IIIb, intra-abdominal lymph nodes
  • C82.44 Follicular lymphoma grade IIIb, lymph nodes of axilla and upper limb
  • C82.45 Follicular lymphoma grade IIIb, lymph nodes of inguinal region and lower limb
  • C82.46 Follicular lymphoma grade IIIb, intrapelvic lymph nodes
  • C82.47 Follicular lymphoma grade IIIb, spleen
  • C82.48 Follicular lymphoma grade IIIb, lymph nodes of multiple sites
  • C82.49 Follicular lymphoma grade IIIb, extranodal and solid organ sites
  • C82.5 Diffuse follicle center lymphoma
  • C82.50 Diffuse follicle center lymphoma, unspecified site
  • C82.51 Diffuse follicle center lymphoma, lymph nodes of head, face, and neck
  • C82.52 Diffuse follicle center lymphoma, intrathoracic lymph nodes
  • C82.53 Diffuse follicle center lymphoma, intra-abdominal lymph nodes
  • C82.54 Diffuse follicle center lymphoma, lymph nodes of axilla and upper limb
  • C82.55 Diffuse follicle center lymphoma, lymph nodes of inguinal region and lower limb
  • C82.56 Diffuse follicle center lymphoma, intrapelvic lymph nodes
  • C82.57 Diffuse follicle center lymphoma, spleen
  • C82.58 Diffuse follicle center lymphoma, lymph nodes of multiple sites
  • C82.59 Diffuse follicle center lymphoma, extranodal and solid organ sites
  • C82.8 Other types of follicular lymphoma
  • C82.80 Other types of follicular lymphoma, unspecified site
  • C82.81 Other types of follicular lymphoma, lymph nodes of head, face, and neck
  • C82.82 Other types of follicular lymphoma, intrathoracic lymph nodes
  • C82.83 Other types of follicular lymphoma, intra-abdominal lymph nodes
  • C82.84 Other types of follicular lymphoma, lymph nodes of axilla and upper limb
  • C82.85 Other types of follicular lymphoma, lymph nodes of inguinal region and lower limb
  • C82.86 Other types of follicular lymphoma, intrapelvic lymph nodes
  • C82.87 Other types of follicular lymphoma, spleen
  • C82.88 Other types of follicular lymphoma, lymph nodes of multiple sites
  • C82.89 Other types of follicular lymphoma, extranodal and solid organ sites
  • C82.9 Follicular lymphoma, unspecified
  • C82.90 Follicular lymphoma, unspecified, unspecified site
  • C82.91 Follicular lymphoma, unspecified, lymph nodes of head, face, and neck
  • C82.92 Follicular lymphoma, unspecified, intrathoracic lymph nodes
  • C82.93 Follicular lymphoma, unspecified, intra-abdominal lymph nodes
  • C82.94 Follicular lymphoma, unspecified, lymph nodes of axilla and upper limb
  • C82.95 Follicular lymphoma, unspecified, lymph nodes of inguinal region and lower limb
  • C82.96 Follicular lymphoma, unspecified, intrapelvic lymph nodes
  • C82.97 Follicular lymphoma, unspecified, spleen
  • C82.98 Follicular lymphoma, unspecified, lymph nodes of multiple sites
  • C82.99 Follicular lymphoma, unspecified, extranodal and solid organ sites
  • C92 Myeloid leukemia
  • C92.0 Acute myeloblastic leukemia
  • C92.00 Acute myeloblastic leukemia, not having achieved remission
  • C92.01 Acute myeloblastic leukemia, in remission
  • C92.02 Acute myeloblastic leukemia, in relapse
  • C92.3 Myeloid sarcoma
  • C92.30 Myeloid sarcoma, not having achieved remission
  • C92.31 Myeloid sarcoma, in remission
  • C92.32 Myeloid sarcoma, in relapse
  • C92.4 Acute promyelocytic leukemia
  • C92.40 Acute promyelocytic leukemia, not having achieved remission
  • C92.41 Acute promyelocytic leukemia, in remission
  • C92.42 Acute promyelocytic leukemia, in relapse
  • C92.5 Acute myelomonocytic leukemia
  • C92.50 Acute myelomonocytic leukemia, not having achieved remission
  • C92.51 Acute myelomonocytic leukemia, in remission
  • C92.52 Acute myelomonocytic leukemia, in relapse
  • C92.6 Acute myeloid leukemia with 11q23-abnormality
  • C92.60 Acute myeloid leukemia with 11q23-abnormality not having achieved remission
  • C92.61 Acute myeloid leukemia with 11q23-abnormality in remission
  • C92.62 Acute myeloid leukemia with 11q23-abnormality in relapse
  • C92.A Acute myeloid leukemia with multilineage dysplasia
  • C92.A0 Acute myeloid leukemia with multilineage dysplasia, not having achieved remission
  • C92.A1 Acute myeloid leukemia with multilineage dysplasia, in remission
  • C92.A2 Acute myeloid leukemia with multilineage dysplasia, in relapse
  • C92.Z Other myeloid leukemia
  • C92.Z0 Other myeloid leukemia not having achieved remission
  • C92.Z1 Other myeloid leukemia, in remission
  • C92.Z2 Other myeloid leukemia, in relapse
  • C92.9 Myeloid leukemia, unspecified
  • C92.90 Myeloid leukemia, unspecified, not having achieved remission
  • C92.91 Myeloid leukemia, unspecified in remission
  • C92.92 Myeloid leukemia, unspecified in relapse
  • C94 Other leukemias of specified cell type
  • C94.0 Acute erythroid leukemia
  • C94.00 Acute erythroid leukemia, not having achieved remission
  • C94.01 Acute erythroid leukemia, in remission
  • C94.02 Acute erythroid leukemia, in relapse
  • C94.2 Acute megakaryoblastic leukemia
  • C94.20 Acute megakaryoblastic leukemia not having achieved remission
  • C94.21 Acute megakaryoblastic leukemia, in remission
  • C94.22 Acute megakaryoblastic leukemia, in relapse
  • C94.3 Mast cell leukemia
  • C94.30 Mast cell leukemia not having achieved remission
  • C94.31 Mast cell leukemia, in remission
  • C94.32 Mast cell leukemia, in relapse
  • C94.4 Acute panmyelosis with myelofibrosis
  • C94.40 Acute panmyelosis with myelofibrosis not having achieved remission
  • C94.41 Acute panmyelosis with myelofibrosis, in remission
  • C94.42 Acute panmyelosis with myelofibrosis, in relapse
  • C94.6 Myelodysplastic disease, not classified
  • C94.8 Other specified leukemias
  • C94.80 Other specified leukemias not having achieved remission
  • C94.81 Other specified leukemias, in remission
  • C94.82 Other specified leukemias, in relapse
  • D46 Myelodysplastic syndromes
  • D46.0 Refractory anemia without ring sideroblasts, so stated
  • D46.1 Refractory anemia with ring sideroblasts
  • D46.2 Refractory anemia with excess of blasts [RAEB]
  • D46.20 Refractory anemia with excess of blasts, unspecified
  • D46.21 Refractory anemia with excess of blasts 1
  • D46.22 Refractory anemia with excess of blasts 2
  • D46.A Refractory cytopenia with multilineage dysplasia
  • D46.B Refractory cytopenia with multilineage dysplasia and ring sideroblasts
  • D46.C Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality
  • D46.4 Refractory anemia, unspecified
  • D46.Z Other myelodysplastic syndromes
  • D46.9 Myelodysplastic syndrome, unspecified

Thank you for the opportunity to provide comments on the proposed coverage policy for Minimal Residual Disease Testing for Cancer.

References were provided for review.

We would like to thank AMP and CAP for their helpful feedback and suggestions regarding this policy.

We have addressed your comments in Responses 1-4 listed above.

8

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

On behalf of Foundation Medicine, Inc. (“FMI”), a world-leading molecular insights company, and the developer of the FoundationOne® CDx comprehensive genomic profiling (CGP) test (“F1CDx”) and the FoundationOne® Liquid CDx blood-based CGP test (“F1LiquidCDx”), I am pleased to submit comments regarding the above-captioned proposed local coverage determination (LCD).

In summary, we appreciate the progressive approach taken by proposing to allow multiple organizations to seek coverage for minimal residual disease (MRD) tests through the established Technical Assessment (TA) process without requiring a product-specific LCD. It is important for Medicare beneficiaries to have timely access to validated, high-quality MRD tests when used for the identification of the recurrence or progression of cancer or for the monitoring of a therapeutic response.

In the Proposed LCD, the following criteria for coverage of MRD testing in cancer is outlined:

  1. If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content) or are not applicable (the patient does not have cancer as defined below)
  2. The patient has a personal history of cancer, the type and staging of which is within the intended use of the MRD test
  3. The identification of recurrence or progression of disease within the intended use population of the test is identified in the NCCN or other established guidelines as a condition that requires a definitive change in patient management
  4. The test is demonstrated to identify molecular recurrence or progression before there is clinical or radiographical evidence of recurrence or progression; and demonstrates sensitivity and specificity of subsequent recurrence or progression comparable with radiographical evidence of recurrence or progression
  5. The test is demonstrated to identify recurrence or progression with sensitivity and specificity that is considerably more accurate than other established (non-MRD) forms of surveillance or monitoring. To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests unless they are required to follow-up or confirm the findings of this test
  6. If the test is to be used for monitoring therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit therapy indicated
  7. If similar MRD tests exist in the market and are covered by this contractor, test performance for the test must be comparable to existing tests
  8. The test satisfactorily completes a technical assessment that will review and confirm the analytical and clinical validity of the test to ensure conditions 1-7 above are met.

In the ensuing comments, we respectfully request clarification on a set of key topics based on the criteria above.

Tests Included in the Scope of the Draft LCD

In the discussion on “Coverage Indications, Limitations, and/or Medical Necessity”, this LCD provides coverage of MRD testing in cancer under selected circumstances. It is our interpretation, based on the criteria outlined, that a test marketed for therapeutic drug monitoring to detect response to therapy would be eligible for coverage under this draft policy if the test evaluates the response by measuring the proportional changes in the amount of available tumor DNA as noted in the “Summary of Evidence” section. However, when stakeholders see references to “MRD testing”, they may first assume that such testing is limited to diagnose of cancer recurrence, and not contemplate these tests’ use in the evaluation of patient response to therapy. To address this issue, we ask for clarification that a test does not need not be specifically marketed as an “MRD test” in order to obtain coverage under this policy, provided the test falls within the description set forth in the “Background” section of the LCD. Also, with this broader definition, FMI also suggests changing the name of the draft LCD to include therapeutic drug monitoring which acknowledges the broader applicability of the testing beyond use in the diagnosis of cancer recurrence.

Accuracy and Comparability

Criterion 5 in the draft policy states the following:

The test is demonstrated to identify recurrence or progression with sensitivity and specificity that is considerably more accurate than other established (non-MRD) forms of surveillance or monitoring.

In the Proposed LCD, it is a requirement that a test demonstrates it is considerably more accurate than other established (non-MRD) forms of surveillance or monitoring. Chapter 13 of the Program Integrity Manual (PIM) establishes that a service is appropriate if it is “[a]t least as beneficial as an existing and available medically appropriate alternative.” The draft requirement for a test to demonstrate that it is “considerably more accurate” than other established forms of surveillance or monitoring is inconsistent with this section of the PIM. FMI understands and agrees that Medicare beneficiaries should receive high-quality care and that poor-performing tests should not be covered under this LCD. However, we disagree with establishing a requirement that a test perform above and beyond the existing non-MRD forms of surveillance and monitoring. As such, FMI recommends the deletion of this proposed criterion for coverage.

However, if the contractor elects to retain this criterion in some form, we recommend that certain revisions and clarifications be made. First, when assessing coverage for tests under this LCD, it proposes to evaluate vis-à-vis other “established” non-MRD forms of surveillance or monitoring. The draft policy does not, however, articulate the standard by which the contractor would consider these forms “established”. FMI requests that the contractor provide an objective, verifiable description of how it defines this status, such as incorporation in a major clinical guideline.

Second, the draft LCD does not address how the contractor will determine whether a test is “considerably more accurate” than established methods. To evaluate the accuracy of the test in relation to other forms, we recommend considering this standard to be met if the test meets any one of the following objective criteria:

  • Higher sensitivity compared to other forms;
  • Higher specificity compared to other forms; OR
  • Similar sensitivity and specificity and either: detection at an earlier point in time (allowing, for example, discontinuation of ineffective therapy earlier and/or a switch to therapy with likely clinical benefit) or a lower adverse event profile compared to the other non-MRD forms.

We further encourage the contractor to confirm that a head-to-head clinical trial would not be required to establish such performance characteristics as compared to the “established” method.

Similarly, for criterion 7, the draft LCD notes the following:

If similar MRD tests exist in the market are covered by this contractor, test performance for the test must be comparable to existing tests.

We ask the contractor to establish a similar, objective standard (e.g., similar sensitivity, similar specificity) when deciding whether a test is “comparable” to existing tests. As such, we request clarification that test developers need not establish comparability via a head-to-head trial and that the data elements and parameters that will be required to demonstrate that the tests are comparable be defined.

Monitoring Therapeutic Response

Criteria 6 notes that where a test will be used for monitoring therapeutic response, the test must “demonstrate the clinical validity of its results in published literature for the explicit therapy indicated.” It is our interpretation that the test must demonstrate the clinical validity of its results for a class of therapeutics whether immunotherapy, targeted therapy or chemotherapy. We ask for a revision in the language in this criterion to clarify the intent.

Requirements for MRD Testing

The Proposed LCD states that MRD testing – whether to detect cancer recurrence or to determine tumor response to therapy – may require two different types of assays as part of the service. Specifically, the testing may include a baseline tumor signature followed by a series of assays taken at various timepoints. We applaud the contractor for acknowledging the multiple components required to perform MRD testing on Medicare beneficiaries with cancer. It is our interpretation that the baseline tumor signature component of MRD testing can be established through previous diagnostic testing on the tumor. More specifically, tumor testing performed to inform therapeutic treatment options (e.g., an assay using NGS methodology that falls under NCD 90.2) can also serve as a baseline tumor signature for the MRD testing that falls under this LCD. We ask the contractor to clarify the coverage of this scenario in the Final LCD.

In summary, we request that the Proposed LCD be revised to clarify the questions and comments raised regarding the criteria discussed above. We appreciate the opportunity to submit comments on this draft coverage guidance and thank you for your consideration.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally –

The title of the policy will not be changed. The applicability of MRD for monitoring therapeutic response is addressed clearly in the policy, in both the Coverage Criteria and Summary of Evidence sections.

As-written, the revised draft policy adheres to the standards of Chapter 13 of the Program Integrity Manual (PIM) which establishes that a service is appropriate if it is “[a]t least as beneficial as an existing and available medically appropriate alternative.” We refer you to Coverage Criteria #4 and #5.

9

The following comment was submitted to Noridian:

This comment is directed towards the draft policy of Minimum Residual Disease (MRD) Testing for Cancer. Thank you for posting this policy and requesting feedback. Liquid biopsy is an area of my own research, and MRD detection is a logical extension of that platform based on available data. I believe that this approach will complement other modalities in improving patient care and I am supportive.

I suggest that some clarifications should be considered. The section related to therapeutic monitoring is unclear to me and could use clarification. As currently written, it appears as if the policy requires clinical validity data for each specific therapy, (i.e., drug or therapy combination). I assume that what you really mean is each drug class, since in some situations there are a large number of individual drugs or combinations all considered equivalent by practicing oncologists as well as guidelines. My assessment of current data is that the ability to identify responders and non-responders using MRD assays seems robust within and across individual drugs and combinations. There may however be differences between cancer types.

Additionally, in the paragraph at the bottom of page 3,1 find the "single test" concept to be confusing. As stated in the paragraph, a series of tests will likely be required, especially given preliminary data suggesting that MRD assays could be negative early on but turn positive on later assessment. This paragraph as currently written also seems to imply that a tissue-based assay will establish the baseline for subsequent plasma-based MRD testing. Please be aware that knowing whether there is, circulating tumor DNA in plasma at baseline is-the standard here, in order to account for variance in tissue-plasma results and "non-shedding" in some patients.

Please consider updating the policy to address these concerns. Thanks again for the opportunity to comment on this important LCD.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

10

The following comment was submitted to Palmetto GBA and Noridian:

The American Society of Hematology (ASH) is pleased to offer comments on the proposed local coverage determination (LCD), Minimal Residual Disease (MRD) Testing for Cancer.

ASH represents more than 18,000 clinicians and scientists worldwide who are committed to the study and treatment of blood and blood-related disease. These disorders encompass malignant hematologic disorders such as leukemia, lymphoma, and multiple myeloma, as well as non-malignant conditions such as sickle cell anemia, thalassemia, bone marrow failure, venous thromboembolism, and hemophilia. In addition, hematologists are pioneers in demonstrating the potential of treating various hematologic diseases and continue to be innovators in the field of stem cell biology, regenerative medicine, transfusion medicine, and gene therapy.

Specifically, ASH is commenting on the following:

  1. First criterion related to Next Generation Sequencing National Coverage Determination
  2. Terminology
    1. Minimum versus minimal
    2. Protease inhibitors versus proteasome inhibitors
  3. Inclusion of Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML)

First Criterion Related to Next Generation Sequencing National Coverage Determination

The first criterion in the LCD limits coverage to only those patients that have “not been previously tested with the same test for the same genetic content”. ASH disagrees and asks for the elimination of this first criterion for MRD testing for blood cancers. The Society believes this language to be confusing and inaccurate. When testing for MRD in a patient with a hematologic malignancy, the treating physician is frequently assessing whether a pre-treatment marker of disease has decreased or disappeared completely. As such, conventional MRD assessment at the end of treatment necessitates that a baseline (or pre-treatment) test already be completed. Moreover, additional assessments of MRD may be required for (1) longitudinal monitoring or surveillance [for example, in patients with Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Chronic Myeloid Leukemia (CML)], (2) to again assess for end of treatment responses in patients receiving multiple/additional lines of therapy, and (3) to determine response prior to allogeneic stem cell transplantation. ASH refers you to the National Comprehensive Cancer Network (NCCN) guidelines for AML and ALL, which support repeated measures of MRD.

Terminology

Minimum versus minimal

In the background section of the LCD, the language refers to “minimum” residual disease. ASH recommends use of the word “minimal” rather than “minimum” as it is more commonly used in the literature and by clinical experts. Additionally, the Society requests the addition of the word “measurable” when describing MRD in the background section. The term “minimal” can be misleading, as even the low-level disease detected may be significant in terms of prognosis and treatment decision-making. The term “measurable” more accurately describes the presence of cancer cells remaining in a patient. The NCCN guidelines use both terms, “minimal” and “measurable”.

Protease Inhibitors Versus Proteasome Inhibitors

In the multiple myeloma (MM) section of the LCD, ASH recommends deleting the term “protease inhibitors” and replacing it with the term “proteasome inhibitors”. Protease inhibitors are a different drug class from proteasome inhibitors. The former are the anti-viral therapies used in HIV infection. The latter are inhibitors of the proteasome, which is a key protein structure in myeloma.

Inclusion of Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML)

The draft LCD states that MRD use in certain hematological malignancies has been well established in the scientific literature and is used as a patient risk stratification tool and to guide treatment decisions. Specifically, the LCD names ALL, MM, and chronic lymphocytic leukemia (CLL). ASH urges the addition of AML and CML to this list of hematologic malignancies in the LCD and would ask that the corresponding ICD-10 codes be added to the relevant Local Coverage Article. For AML, the goal for all patients should be to achieve a complete remission without MRD after chemotherapy. MRD testing for AML is prognostically important, since survival and relapse-free survival are significantly lower in patients with MRD. In addition, MRD testing can help to determine if a patient should be referred for allogeneic hematopoietic cell transplantation (HCT) to increase the chance of curing the underlying AML. In CML, molecular testing primarily consists of longitudinal polymerase chain reaction (PCR)- based monitoring; well-established targets for molecular testing changes over time guide therapeutic decision-making, including the need to switch therapies or refer for allogeneic HCT.

Thank you for the opportunity to provide comments on the proposed LCD, Minimal Residual Disease Testing for Cancer. This is an extremely important tool in the treatment of patients with hematologic cancers and we appreciate the thoughtful approach taken in the LCD.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally -

1. We agree and have changed ‘minimum’ to ‘minimal.’

2. To address the significant issue of pre-clinical (or subclinical) yet present residual disease, we have added the word ‘biological’ such that Coverage Criterion #4 now reads: The test is demonstrated to identify molecular recurrence or progression before there is clinical, biological, or radiographical evidence of recurrence or progression...

We have also added ‘biological’ to the Summary of Evidence such that it now reads:

MRD testing can be used to:

  • diagnose cancer progression, recurrence, or relapse before there is clinical, biological, or radiographical evidence of progression, recurrence, or relapse
  • detect tumor response to therapy by measuring the proportional changes in the amount of available tumor DNA

3. We agree and have changed ‘protease inhibitors’ to ‘proteasome inhibitors.’

11

The following comment was submitted to Palmetto GBA and Noridian:

Thank you for the opportunity to comment on MolDX: Minimal Residual Disease Testing for Cancer draft, which proposes limited coverage for tests detecting Minimal Residual Disease in patients with cancer.

The proposed LCD is a major step toward increasing access to medically necessary services to detect residual disease and recurrence prior to currently available techniques and monitor therapeutic response. We believe that this testing modality will provide considerable benefit to Medicare beneficiaries by detecting recurrences faster and enabling the ordering physician to make treatment changes to positively impact the patients’ health.

That said, there are a few areas that we would propose minor modifications and clarification to enable companies to develop products to better treat Medicare beneficiaries. These areas are in the fifth coverage bullet point around precluding other surveillance testing and the sixth coverage bullet point around therapeutic monitoring. Our specific comments on these topics are listed below.

1. Clarification of the logistics behind precluding other monitoring tests

  • Current language: To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests unless they are required to follow-up or confirm the findings of this test
  • Requested language: To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests based on molecular ctDNA

Requiring preclusion of all other potential surveillance or monitoring tests that could range from a simple blood-based protein biomarker measurement through a complex molecular test is simultaneously broad and restrictive, potentially generating confusion rather than providing direction. The proposed updated language provides greater clarity and prevents duplicative testing of the same analyte while allowing treating clinicians discretion to direct the appropriate care of their patients.

Additionally, it is important to note that laboratories do not treat patients directly and are subject to the information provided by ordering physicians related to the care that is provided. In order to ensure that the coverage requirements are met and auditable it would be helpful to clarify how companies can demonstrate that these requirements were met in order to pass a CERT, UPIC or other types of audit.

One of the hardest points to prove in an audit is the lack of something. In this instance the lab submitting the claim would need to demonstrate the lack of additional tests ordered for the treatment of the patient. Considering labs do not have access to the Medicare claims database to determine if other services have been billed for, the only objective way to determine that the lack of something is present is through an attestation from the ordering physician on the test order. It would be helpful for Medicare contractors that create coverage requirements which require proof of the lack of something, also provide auditors information surrounding appropriate support to demonstrate that the requirements are met.

UPIC auditors can be very strict in denying services like these. Historically we have seen denials in a UPIC audit stating that a medical record at the time of the order other than the test requisition did not specifically detail proof that other tests could not be run. It is important to note that most ordering physicians in their medical records will sometimes state what test they are ordering but will not document what tests that they are “not” or could not order.

As a solution we propose that when MACs create coverage requirements that must demonstrate the absence of something, that guidance is provided to auditors on how to obtain this information. A signed physician attestation to the coverage element on a test order should be viewed as sufficient proof to demonstrate that the coverage element is fulfilled. Especially if it is something that is not commonly documented in physicians’ chart notes.

2. Discussion about therapeutic monitoring

  • Current language: If the test is to be used for monitoring therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit therapy indicated
  • Requested language: If the test is to be used for monitoring therapeutic response, it must demonstrate the clinical validity in the patient’s clinical diagnosis (e.g., NSCLC) in published literature

There is ample literature spanning multiple individual therapies and multiple therapy classes documenting that decreasing vs. increasing ctDNA levels early on treatment consistently predicts longer vs. shorter progression free and overall survival. While we agree that the test being used for monitoring must demonstrate clinical validity via peer-reviewed publication/s, requiring individual publications for each explicit therapy is unrealistic given the number of explicit therapies approved for solid cancers in addition to all of the permutations potentially available when approved therapies are used in combination with one another. This would unduly restrict access to care given the existing literature and in general the requirement would be hard for multiple test providers to meet due to the requirement from peer reviewed journals that information included in their publications must be novel information, not previously published. Substituting one brand of test has the same performance in a clinical diagnosis would not be considered novel enough for publication in most journals.

Thank you for providing this opportunity to comment. We believe that this proposed LCD is an important advance that will improve the care of Medicare patients with resected cancers by ensuring access to testing that can assist with the detection of recurrence earlier than currently available technologies. We are committed to improving the care of such patients and welcome every chance to do so.

One Table and Several References and were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally -

Regarding how to demonstrate the absence of something – A MRD test does not preclude all other monitoring tests, so long as they fulfill the criteria set forth in the policy (see revised Coverage Criterion #5). As with most diagnostic tests, it is expected that the medical record contains documentation of the medical necessity of the tests performed. Further, the associated Billing and Coding Article states: The medical record must contain clear documentation of the medical necessity of this test, as per the conditions outlined in the policy.

12

The following comment was submitted to Palmetto GBA and Noridian:

Fight Colorectal Cancer (Fight CRC) is a leading advocacy organization dedicated to fighting to cure colorectal cancer and serving as relentless champions of hope for all affected by this disease. On behalf of Fight CRC and select members of our Medical Advisory Board, we are writing today to express strong support for the current Draft LCD issued by MOLDX for the indication of immunotherapy treatment response monitoring using circulating tumor DNA (ctDNA).

Recent ctDNA technology advancements are encouraging and have the ability to help identify patients for whom treatment regimens may or may not be effective. With an increasing number of cancer patients being prescribed immunotherapies, a sensitive tool that can accurately assess and characterize response is of great need.

As patient advocates, access to ctDNA for immunotherapy response monitoring through Medicare coverage would support a shared goal of improving patient care by enabling characterization of immunotherapy response not otherwise available, limiting unnecessary toxicity exposure and reducing patient costs.

We support the current Draft LCD issued by MOLDX with a request that optimal test characteristics of high sensitivity and specificity through serial monitoring are uniform across the covered tests. We look forward to learning about your decision and being a partner in dissemination of new options for patients and other stakeholders. We are grateful for your attention to this matter.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally –

Optimal performance characteristics (such as sensitivity and specificity) for tests covered under this policy are addressed in Coverage Criteria #4 and #10.

13

The following comment was submitted to Noridian:

I am writing in support of the Medicare draft LCD for Signatera MRD assay for treatment response monitoring in patients with solid tumors, receiving immunotherapy. I am a medical oncologist at Arizona Oncology in the community setting where I see patients with all types of cancer. After caring for patients for many years in this setting, I see the value of effective therapies and also a need for a sensitive disease monitoring tool to prevent over treatment.

As the landscape of immunotherapy continues to grow exponentially, the need for sensitive response monitoring tools grows along with it. We know that response rates to immunotherapy even in eligible patients are low. For example, in NSCLC only about 25% of eligible non-small cell lung cancer patients respond to immune checkpoint inhibitors. Furthermore, we realize that these therapeutics are not without risk. Adverse events associated with immune therapy can be severe to fatal, with its frequency and severity expected to worse as the patient continues to stay longer on an ineffective treatment. With these concerns in mind, I find Signatera, a ctDNA-based assay that can track the treatment efficacy in terms of response to be very effective.

I am personally impressed with Signatera's technology. It is a personalized, and tumor informed multiplex PCR, NGS assay that has published clinical validity to detect ctDNA at molecular level in multiple tumor types. The currently used biomarkers such as PD-L1 expression and TMB status are not efficient for tracking treatment response. This was well illustrated in the recent Nature Cancer publication that demonstrated change in ctDNA from baseline was the only significant biomarker for predicting overall survival and progression free survival (PFS) in a multivariate analysis over PD-L1 status and TMB. Most importantly, an increase or decrease in ctDNA levels after just six weeks on treatment was a significant predictor of PFS and OS. This study strengthens Signatera's utility as a sensitive, predictive and a prognostic indicator of outcomes, demonstrating superior performance over other biomarkers.

This in my opinion is an invaluable tool that can provide oncologists with the insight to avoid unnecessary treatment, pivot to treatment that might be more effective, and ideally improve the lives of patients through better outcomes. I, hereby, provide full support for Medicare coverage of Signatera, ctDNA assay.

Thank you for your thoughtful comments and support of this policy.

14

The following comment was submitted to Noridian:

I have reviewed the coverage criteria and I feel that this policy will continue to move treatment for oncology forward. However, I am concerned that Medicare is imposing a requirement that the use of this type of testing must preclude other forms of testing. I don’t feel that there is redundancy in MRD testing vs other types of testing. Please narrow the definition for precluding other testing to be other MRD tests instead of all monitoring tests which is vague and overly restrictive.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above. Specifically, we have revised the language in Coverage Criteria #4 and #5 such that the policy does not restrict tests that provide non-redundant information.

15

The following comment was submitted to Noridian:

Thank you for considering our comments on MolDX: Minimal Residual Disease Testing for Cancer. GRAIL, Inc. (GRAIL) is a healthcare company whose mission is to detect cancer early, when it can be cured. We are focused on alleviating the global burden of cancer by developing pioneering technology to detect and identify multiple deadly cancer types early. GRAIL is using the power of next-generation sequencing, population-scale clinical studies, and state-of-the-art computer science and data science to enhance the scientific understanding of cancer biology. GRAIL is developing products that address significant unmet medical needs in multi-cancer detection. GRAIL is developing diagnostic applications, including a minimal residual disease (MRD) test, designed to enable blood-based detection with or without tissue, and without the need for a personalized assay.

GRAIL supports the coverage of minimal residual disease testing for cancer, which we believe is an important step forward to guide treatment and detect disease recurrence, and we commend the hard work of the multiple contractors who have collaborated to bring this draft LCD forward. We also support a streamlined approach to coverage where individual test developers can seek coverage for specific tests under a technical assessment process without requiring reconsideration of the LCD. In this vein of support, we would like to recommend some modifications to the draft LCD that we think will provide clarity while keeping with the intent of the draft LCD.

1. We request clarification as to how MolDX defines an MRD test or assay under this coverage policy.

1a. We recommend clarifying that LCD coverage does not require a tissue-based test to establish a tumor signature prior to MRD blood testing.

The draft LCD describes an approach to MRD testing in which a tissue-based test is required initially to establish a tumor signature prior to blood or serum testing. We believe this language describes one approach to MRD testing and is not intended to be a strict requirement that all MRD testing must have an initial tissue-based test to qualify for LCD coverage. It is possible to establish a tumor signature without a tissue assay (including for solid tumors). Since tests capable of establishing a tumor signature are coming to the market, we recommend that the final LCD clarify that coverage does not require an initial tissue-based sample, and that all MRD tests, including those that include a pretreatment liquid biopsy and those that do not require a baseline sample, are eligible for coverage provided analytical and clinical validity are shown.

1b. We recommend that MolDX clarify that additional MRD assays, even in patients who have cancer, may be tests for new genetic content.

The concept of considering a single episode of MRD testing to involve multiple assays was developed by LCD/article. This LCD, however, was superseded by a revision to NCD 90.2 that became effective on January 27, 2020. Under the revised NCD 90.2 text, there is no prohibition on covering the same test for the same cancer. Specifically, the new NCD language permits coverage of follow-up testing for the same cancer when the patient has “not been previously tested with the same test using NGS for the same cancer genetic content.”

Minimal residual disease testing involves looking for alterations in relative quantities of particular molecular signatures. As such, MRD assessment using sequencing technology is based on the measurement of quantitative changes in molecular content in the blood (i.e. subsequent assays are not testing for the same genetic content). New methods to MRD testing are in development that look at specific changes in molecular content which can accomplish the same clinical goal of MRD testing. We recommend that this LCD clarify that multiple instances of testing for MRD may be obtained using the same test for the same cancer, when the test is ordered to look for a change in molecular content.

Based on our comments from 1a and 1b, we recommend that the final paragraph in the section on Coverage Indications, Limitations, and/or Medical Necessity be modified as follows:

For patients with cancer:

Minimal residual disease testing may be performed in a number of ways. Some tests rely on tissue assay to establish a tumor signature, while other tests may establish a signature from blood and other bodily fluids. For example, MRD testing currently requires two types of assays to be performed as part of the service. First, a sample may be used to establish a baseline tumor signature as defined by the test methodology. This is followed by a series of assays run on blood or other bodily fluids to detect the presence or recurrence of tumor based on the measured biomarkers, expression, or other analytes over various time points. For some tests this series of assays has been considered by MolDX to comprises a single test when the patient is known to have cancer. However, MolDX expects that for future tests requesting coverage, each test instance will comprise a single assay, unless the laboratory or manufacturer producing the test presents a compelling reason to bundle multiple assays into a single episode of testing. Follow up MRD assays with the same test will be considered to be tests for new genetic content.

When the patient is NOT known to have cancer (specifically when there is no clinical, radiographical, or other biological evidence that tumor cells remain post treatment and subsequently the patient is no longer being subjected to therapeutic interventions for cancer), a second kind of test may exist wherein a single additional timepoint may constitute a single test.

2. We recommend that MolDX periodically update the technical assessment for covered tests in the related coverage article and not mandate a new or revised LCD for each test.

As noted above, we support granting coverage following submission and review of a technical assessment document showing analytical and clinical validity of the specific test at issue. This streamlines the current process, which requires a new LCD or reconsideration of an existing LCD for coverage of each new test.

As MolDX moves away from product-specific LCDs, it is still critical that MolDX make public which tests are covered as both a matter of transparency, and so that clinicians and other payers are able to easily determine which tests have met MolDX’s requirements. We believe that coverage articles associated with LCDs are an appropriate mechanism to do that, and we recommend that MolDX publish the list of covered tests under a coverage article process.

3. We recommend that MolDX evaluate new MRD tests based on their ability to inform management rather than comparing new MRD tests to already covered MRD tests.

We agree that Medicare should only pay for high quality services. MolDX is planning to operationalize this intent in part with the requirement that “performance for the test must be comparable to existing tests.…” We believe that this particular approach will either not be something that MolDX can meaningfully implement, or the implementation will result in inappropriate comparisons between tests.

Performance criteria should take into account patient needs, the methodology, and the indications for testing. For example, in patients where a tissue biopsy is too risky to obtain or tissue quality may be poor, a MRD test may still have utility even if it does not have comparable performance to MRD tests that rely on a tissue biopsy. Additionally, even among tests with similar indications, selection of different genetic targets or capture methods may result in different analytical performance in ways that do not impact clinical performance. Finally, the definitive methods for comparing performance of services are equivalence or non-inferiority comparative effectiveness studies. Requiring such studies could be practically impossible (both technically and economically) and create virtual monopolies for the first tests to the market in each cancer type by requiring subsequent tests to conduct comparative effectiveness studies that are complex, time consuming, and extremely costly to implement.

We recommend that rather than compare test performance among MRD tests, MolDX consider the test performance of any given test within the context of the clinical questions that test is intended to address, the specific analytical methods of each assay, and the specific molecular content addressed. MolDX can then assess whether the level of performance displayed by the test is sufficient to address the clinical questions the test is intended to answer within the intended use population.

Thank you for considering our comments.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally -

As a matter of transparency, MolDX will maintain a published record of covered (non-single-gene PCR) MRD tests. Please refer to the related Billing and Coding Article.

16

The following comment was submitted to Noridian:

This letter is in response to the request for comments related to the Minimal Residual Disease draft LCD. I would like to offer my support for this LCD and commend the authors for creating a future-proofed LCD to accommodate new technologies devoted to the management oncology patients. I would like to offer a minor modification to the coverage requirement to clarify what tests can be used for therapeutic monitoring.

Specifically, the requirement for the test to have published clinical validity for “the explicit therapy indicated” would be overly restrictive. Considering the diversity of FDA- approved agents even for rare molecular subtypes within each indication, I can only conclude that this requirement will make it impractical to enact these technologies fairly and widely. Consider, for instance, that there are nine NCCN-approved regimens for EGFR activating mutation-positive NSCLC, and four approved regimens for ALK- fusion-positive cases, which represent no more than 2% of all NSCLC cases. I highly recommend that you change this requirement to be indication-specific and not therapy- specific so as to allow appropriate access to care.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

17

The following comment was submitted to Noridian:

The PALTOWN Development Foundation is committed to expanding its unique model of online peer-to-peer health communities to provide hope and empowerment to patients and caregivers in the colorectal cancer (CRC) space and across other disease states. The PALTOWN Development Foundation supports COLONTOWN, a community of over 5,400 CRC patients and caregivers from around the world, and we would like to show our strong support for the current Draft LCD for the indication of immunotherapy treatment response monitoring issued by MOLDX.

We are not only patient advocates, but most of our volunteers and staff are also cancer patients, survivors and caregivers. We continue to passionately advocate for our members who are searching for the appropriate information and resources. We are excited for the potential Medicare coverage of immunotherapy treatment response monitoring. Applicability of such tests to monitor treatment response to immunotherapy has recently been published. Such tests enable patients to stay on immunotherapy treatments that are efficacious and get off those that are not, without getting exposed to unnecessary side-effects on non-efficacious therapies.

Coverage for these innovative technologies for therapy response monitoring are much appreciated by the patient and caregiver community. Our members are also concerned about the cost of tests and treatments throughout their treatment plan and covering ctDNA testing would allow many of them to have access to these tests and thereby ensure appropriate and affordable therapy is prescribed.

Many of our members are already working with clinicians to provide ctDNA testing like Signatera, while undergoing immunotherapy treatment. We support the current Draft LCD issued by MOLDX and look forward to positive determination soon. Thank you for your time.

Thank you for your thoughtful comments and support of this policy.

18

The following comment was submitted to Palmetto GBA and Noridian:

Adaptive Biotechnologies Corporation (Adaptive) appreciates the opportunity to comment on the proposed Local Coverage Determination (LCD): MolDX: Minimal Residual Disease Testing for Cancer. We support the establishment of an LCD for minimal residual disease (MRD) testing in cancer and thank Noridian and the MolDX program for drafting a policy intended to keep pace with rapidly growing evidence on the importance of MRD testing to improving patient outcomes across many cancers.

Adaptive, a public company founded in Seattle, WA in 2009, is a pioneer and leader in combining high- throughput sequencing and expert bioinformatics to profile T-cell and B-cell receptors, referred to as immunosequencing. The mission of Adaptive is to translate immunosequencing discoveries into clinical diagnostics and therapeutics to improve patient care. Adaptive’s clonoSEQ® Assay is a next generation sequencing (NGS)-based assay for the assessment of MRD in patients diagnosed with lymphoid malignancies. This assay evaluates lymphoid clonal distribution and expansions by identifying the DNA sequence(s) associated with a malignancy and then assessing the presence of these sequence(s) in subsequent samples to monitor changes in burden of disease during and after treatment, evaluate risk, and predict clinical outcome.

clonoSEQ® is available as an FDA-cleared in vitro diagnostic (IVD) test provided by Adaptive for use in B-cell acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) patients to detect and monitor MRD. clonoSEQ® is the first and only MRD assay to obtain FDA clearance for any lymphoid cancer indication. clonoSEQ® is also available for use in other lymphoid cancers as a CLIA-validated laboratory developed test (LDT) service. clonoSEQ® is covered by Medicare and commercial payers in the US, and the assay is used by hematologist-oncologists across the country in the care of patients with lymphoid cancers.

Below we provide comments on the proposed coverage policy, which generally reflect three main principles:

  1. We are supportive of the continued coverage for NGS MRD testing in ALL, MM, and CLL, as outlined in the draft LCD. We also note the available and rapidly growing evidence base for MRD assessment in patients with other lymphoid malignancies (detailed below) and encourage Noridian and MolDX to consider perspectives from the clinical community who are incorporating MRD when treating these patients, as you finalize this LCD.
  2. We believe that a foundational LCD for MRD testing in both hematologic and solid cancers and for a wide range of NGS-based tests is a viable approach; however, the LCD could be improved to better recognize and reflect the differences between different cancer types and different tests. Given this diversity, it is critical for the LCD to clearly outline the standards that need to be met for new tests leveraging a similar technology to a test for which coverage was initially established.
  3. The draft LCD establishes coverage of MRD as a “series of assays” in a patient with cancer, which we agree can be a viable approach if needed. However, we believe that this approach is not required given the new language of NCD 90.2 following the reconsideration. Instead, MRD should be covered on a per- test basis, in accordance with how Medicare covers MRD assessment performed by other technologies.

SPECIFIC COMMENTS

Relevant LCD Text

Coverage Indications, Limitations, and/or Medical Necessity

This Medicare contractor will provide limited coverage for molecular circulating tumor DNA (ctDNA) tests that detect minimum residual disease (MRD) in patients with a personal history of cancer.

  1. If Next-Generation Sequencing (NGS) methodology is used in testing, the conditions set by NCD 90.2 are fulfilled (summarized: the patient has advanced cancer; plans on being treated for said cancer, and has not been previously tested with the same test for the same genetic content) or are not applicable (the patient does not have cancer as defined below)
  2. The identification of recurrence or progression of disease within the intended use population of the test is identified in the NCCN or other established guidelines as a condition that requires a definitive change in patient management.
  3. The test is demonstrated to identify molecular recurrence or progression before there is clinical or radiographical evidence of recurrence or progression; and demonstrates sensitivity and specificity of subsequent recurrence or progression comparable with radiographical evidence of recurrence or progression.
  4. The test is demonstrated to identify recurrence or progression with sensitivity and specificity that is considerably more accurate than other established (non-MRD) forms of surveillance or monitoring.
  5. To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests unless they are required to follow-up or confirm the findings of this test.
  6. If the test is to be used for monitoring therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit therapy indicated.
  7. If similar MRD tests exist in the market and are covered by this contractor, test performance for the test must be comparable to existing tests.
  8. The test satisfactorily completes a technical assessment that will review and confirm the analytical and clinical validity of the test to ensure conditions 1-7 above are met.

MRD testing often requires two types of assays to be performed as part of the service. First, a sample is taken from tumor diagnostic material to establish a baseline tumor signature as defined by the test methodology. This is followed by a series assays run on blood to detect the presence or recurrence of tumor based on the measured biomarkers, expression, or other analytes over various timepoints. This series of assays comprises a single test when the patient is known to have cancer.

Comments

MRD assessment is not limited to ctDNA. For hematologic cancers, and specifically lymphoid cancers, the assessment of MRD is based on direct measurement and quantification of cancerous cells from a bone marrow or blood sample. For example, clonoSEQ® is an MRD test for lymphoid cancer that assesses DNA from a cellular source (genomic DNA from blood or bone marrow) or a cell-free source (ctDNA from plasma).

This statement should be revised to make clear that coverage also applies to tests that assess MRD by direct quantification of malignant cellular material:

“This Medicare contractor will provide limited coverage for molecular DNA tests that detect minimal residual disease (MRD) in patients with a personal history of cancer.”

This LCD appears to be specific to NGS-based testing for MRD, which we believe is appropriate. We request a clarification of this point in the final LCD.

Also, we note that when an MRD test is ordered by a clinician treating a patient with cancer, the “cancer genetic content” being sought by the test is the quantitative level of cancer present in the patient, which is expected to change related to treatment and throughout the course of disease. Each MRD assessment along the patient’s care continuum is, by definition, testing new genetic content, when ordered at clinically relevant timepoints (e.g., timepoints that would provide opportunity for cancer quantity to change or other timepoints supported by guidelines). See below for additional details.

We agree that guidelines are an important element for consideration in the coverage determination for MRD testing, and we support the referencing of NCCN or other established guidelines as part of the LCD’s coverage criteria.

We note that for several hematologic cancers, NCCN guidelines already include 2A or higher recommendations for MRD assessment by NGS or other technologies. We believe inclusion of MRD testing in established guidelines should be sufficient to support coverage in most cases, without requiring the additional criteria put forth in criteria 3-6. To that end, we recommend adding the following text to this criterion:

“MRD assessment by the technology being considered for coverage is supported by NCCN or other established guidelines; or the identification of recurrence or progression of disease within the intended use population of the test is identified in the NCCN or other established guidelines as a condition that requires a definitive change in patient management.”

We agree with the first part of the criterion. Indeed, in lymphoid cancers, MRD testing has been established as a standard method to detect disease below the limit of traditional surveillance methods, including imaging.

However, the second part of the criterion (requiring a demonstration of sensitivity and specificity compared to radiographical evidence) is not uniformly applicable across cancers. In some lymphoid cancers (see examples below), radiological methods are not used to detect recurrence or progression, and thus it would not be an appropriate comparator and should not be a factor for coverage decisions.

For example, according to the NCCN Guidelines for ALL, PET/CT is only used at diagnosis to rule out suspected lymphocytic lymphoma. For CLL, NCCN Guidelines recommend PET at diagnosis to direct the nodal biopsy if histological transformation is suspected. PET is not used post diagnosis in either disease for surveillance to detect recurrence or progression.

For myeloma, NCCN Guidelines recommend imaging in addition to MRD testing, as part of a complementary response assessment criteria, with imaging only being done after MRD negativity has been confirmed. Additionally, the primary rationale for imaging studies in myeloma is for the assessment of lesions and not to detect recurrence or progression.

As the second half of this criterion is not uniformly applicable across lymphoid malignancies, we recommend the addition of clarifying language, such as:

“This criterion applies only to solid tumors or in specific hematologic cancers where progression/recurrence assessment by radiological imaging is standard, as defined in guidelines.”

Adaptive agrees that this criterion is important to support coverage decisions and offers the following evidence related to lymphoid cancers.

In the past, the goal of treatment in MM, ALL, CLL, and non-Hodgkin's lymphoma (NHL) has been to achieve a “complete response” (CR) based on morphologic, surrogate markers, and/or imaging. It is now clear, however, that conventional CR is an insufficient definition of response. Many patients who achieve CR using conventional methods still harbor MRD, and the presence or recurrence of MRD is significantly more predictive of poor outcome (relapse and ultimately death), independent of treatment regimen or time point of assessment.

Recent large meta-analyses in MM, ALL, and CLL have confirmed the importance of MRD assessment during treatment, and updates to both national and international clinical practice guidelines for myeloma, ALL, and CLL reflect a corresponding shift in response assessment criteria by adding MRD to existing response metrics.

In lymphoma, ctDNA has shown to be present in patients in a CR and the presence of ctDNA has been shown to be prognostic of worse outcome.

ctDNA has also been shown to be more sensitive than serum lactate dehydrogenase at assessing presence of disease.

Assessing MRD in hematologic cancers should not necessarily preclude other standard forms of disease monitoring, which may provide oncologists with other useful clinical information about the patient. Some other standard response tools are a complement to MRD testing, and both provide unique clinical value.

For example, in myeloma, imaging is commonly used to look for lytic lesions in the skeletal system, which cannot be assessed by MRD. In ALL, assessment of extramedullary disease or CNS involvement is part of the standard response assessment criteria, which is not found by MRD assessment of the blood or bone marrow. In NHL and CLL, organ and lymph node size are part of standard response assessment, which is separate from MRD assessment. In addition, imaging is used to identify the site of disease, which cannot be assessed by MRD alone.

As clinicians use MRD as a complement to other non-MRD surveillance and monitoring tools, we suggest that this criterion be removed altogether. If the criterion is not removed, it should include additional language to allow complementary testing for surveillance or monitoring when standard-of-care, for example:

“To be reasonable and necessary, it must also be medically acceptable that the test being utilized precludes other surveillance or monitoring tests intended to provide the same information unless they are required to follow- up or confirm the findings of this test.”

We are concerned that this requirement is based on generalizations of solid tumor management paradigms to hematologic malignancies. We recommend that validation requirements for MRD testing in hematologic malignancies align with the guideline-recommended treatment paradigms for these patients to ensure that tests will be validated to provide clinically utile information.

The role for nearly all guideline-recommended surveillance in lymphoid cancers is to monitor an individual’s response following a potentially diverse continuum of therapeutics or interventions, such as a stem cell transplant, to inform patient management. There is a large and expanding literature base demonstrating the use of MRD in hematologic cancers to measure depth of response to treatment that is independent of the specific intervention applied.

The criterion as written should only be applied when MRD assessment is tied to the monitoring of a specific therapeutic product (i.e., a companion diagnostic use).

We support the requirement for assays to demonstrate clinical validity of their results in published literature; however, we recommend striking “for the explicit therapy indicated” from the criterion.

It is critical that tests used in the management of patient care establish robust analytical and clinical performance metrics. As there are many different methodologies among the NGS MRD tests potentially captured under this policy, we believe it is essential for Noridian and MolDX to provide additional detail that is specific to the different methodologies.

For example, as regards analytical validity, in hematologic malignancies, an immunosequencing assay (such as clonoSEQ®) is a unique type of MRD test that would have a specific set of performance metrics that other immunosequencing tests being considered for coverage should be evaluated against.

At a minimum, analytical validation studies should assess:

  • DNA extraction methods for all sample types being assessed
  • Linearity
  • Limit of detection
  • Limit of quantitation
  • Limit of blank
  • Precision
  • Accuracy
  • Cross-contamination
  • Interfering substances
  • Sample stability
  • Reagent stability
  • Calibration rates of initial diagnostic sample to enable MRD assessment, by disease (if applicable)

We agree with this criterion and suggest that any covered tests meet the rigor suggested above. In particular, we recommend that you clarify in the final LCD that new tests utilizing a similar methodology to a test for which existing coverage exists should be required to demonstrate equivalent or better test performance across all of the domains outlined above to obtain coverage.

Adaptive expects that the technical assessment and the specific analytical performance criteria required should be specific to the methodology of test seeking coverage (as we describe above).

The draft LCD establishes coverage of MRD testing in a patient with cancer as a baseline assay plus a series of assays that comprise a single test, or “episode”. This approach for MRD coverage, while viable if needed, is problematic and will become increasingly challenging over time. Specifically, the approach:

  • Requires continuous assessment and updating by contractors, labs, and the clinical community, across each cancer type to ensure that the number of assessments in the “series of assays” is consistent with guidelines and current clinical practice
  • Is inconsistent with how Medicare covers MRD assessment by other non-NGS technologies, such as flow cytometry-based or PCR methods
  • Is very complicated for labs to operationalize and manage, even for labs with a focused expertise in performing MRD tests
  • Creates significant challenges with statutorily mandated PAMA updates to pricing. While the LCD is not intended to be a pricing document, this coverage language has the effect of defining the unit of service priced. Since the unit of service priced here is an episode, and because this is inconsistent with how commercial payers pay for such services (commercial payers typically pay on a per-assay basis), it would result in PAMA-reported data that is not reconcilable with Medicare's unit of pricing. For any tests that obtain CPT codes, it will be challenging for CMS to carry out the statutory mandate updating CLFS prices based on private payer data in a way that is both legal and logical.
  • Limits the ability for CMS, labs, and researchers to track NGS MRD usage patterns in real world clinical practice

We believe, however, that the proposed episode approach is not necessary under the revised NCD 90.2’s new “cancer genetic content” language, which recognizes that there are cases when a patient with the same primary diagnosis should receive the same test again.

The NCD 90.2 revision appears to allow MAC discretion to cover repeat testing with the same NGS test when the patient has "not been previously tested with the same test using NGS for the same cancer genetic content."

We believe the intent of the new NCD language is to allow repeat testing, when reasonable and necessary, but to limit duplicative testing that would not be expected to yield new, actionable information. We support this approach.

When an NGS MRD test is ordered by a clinician treating a patient with cancer, the specific “cancer genetic content” being sought by the test is the quantitative level of cancer present in the patient, which is expected to change related to therapeutic intervention and throughout the course of disease. Each MRD assessment along the patient’s care continuum is, by definition, testing new genetic content, when ordered at clinically relevant timepoints (e.g., timepoints that would provide opportunity for cancer quantity to change or timepoints supported by guidelines).

We believe the NCD 90.2 “cancer genetic content” language enables contractor discretion to cover NGS MRD assessments on a per-test basis, and we urge Noridian and MolDX to reflect this in the final LCD.

Background

-detect tumor response to therapy by measuring the proportional changes in the amount of available tumor DNA

The description of MRD assessment and the relevant MRD technologies should be inclusive of applications in hematologic cancers, where MRD assessment is commonly based on direct measurement of tumor cells in bone marrow or blood samples, and where techniques such as immunosequencing have enabled more standardized, specific and sensitive MRD assessment, as well as methods that leverage relative amounts of tumor-derived genetic material circulating in the blood of both solid tumor and hematologic cancer patients.

To ensure applicability, we recommend modifying this criterion to read:

“detect tumor response to therapy by measuring the proportional changes in the amount of tumor cells or available tumor DNA”

ADDITIONAL INFORMATION: MRD IN HEMATOPOIETIC MALIGNANCIES

We are supportive of the continued coverage for NGS MRD testing in ALL, CLL, MM, as outlined in the draft LCD. This continuation of Medicare coverage is consistent with the broad evidence base supporting the use of MRD in these conditions and with established clinical guidelines. Additional publications and guideline citations across these cancer types are provided in the references at the end of this comment letter, if of relevance to Noridian and MolDX.

We also note the available and rapidly growing evidence base for MRD assessment in patients with other lymphoid malignancies. We encourage Noridian and MolDX to consider perspectives from the clinical community who are incorporating MRD when treating these patients, as you finalize the conditions covered under this LCD. Specifically, we would encourage Noridian and MolDX to consider the following evidence for use of NGS MRD in NHL.

Non-Hodgkin’s Lymphoma

In lymphoma, MRD refers to detection of disease below the limit of traditional surveillance methods, including imaging. Imaging is costly, suffers from false-positive results, has low specificity, exposes patients to radiation, is invasive, lacks a clear correlation with outcome, and has constraints on frequency of use. Due to this, it is not an ideal monitoring modality in lymphoma. Additionally, findings from a retrospective study suggested that surveillance CT may be no better than careful history and examination of the patient, so more effective monitoring technologies are needed.

Monitoring of ctDNA in lymphoma can overcome many of these limitations and aid in assessment of MRD, prognostication, customization of therapy, monitoring for relapse, and consideration of early intervention, while reducing radiation exposure.

Clinical Data in Support of ctDNA Assessment

Kurtz et al. showed that ctDNA demonstrated improved specificity, with no false positives identified (100% vs 56%, P<0.0001) and similar sensitivity to predict relapse (31% vs 55%, P=0.4) compared with PET/CT. ctDNA was also more sensitivity than LDH and at assessing presence of disease (59% vs. 88%; P=0.01). Additionally, the analysis showed that ctDNA by NGS preceded PET/CT detection of relapse by a median lead time of 88 days (range 14-162 days) in patients initially achieving remission. The authors note than in patients who ultimately became ctDNA-positive, many had prior ctDNA-negative results, indicating that this assay is best used serially for disease monitoring rather than a one-time test for presence of disease.

Roschewski et al. assessed ctDNA from 107 patients in a CR during surveillance. Of the 17 patients whose disease relapsed, ctDNA was positive in 15 of the patents with a median lead time of 3.5 months prior to clinical/radiographic relapse. Of the 90 patients who did not progress, 88 (98%) never developed ctDNA. Additionally, ctDNA was predictive of PSF (P<0.0001).

Finally, ctDNA assessed during surveillance identified patients at a high risk for progression (P<0.0001). The authors conclude that “surveillance ctDNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse”, that ctDNA may provide a favorable alternative or complement to interim PET, and “unlike imaging, testing of ctDNA is a non-invasive and dynamic method.”

Herrera et al. assessed 88 lymphoma patients who underwent allogeneic HCT. In this study, 19 patients ultimately developed clinical relapse or progression. Molecular relapse was identified (using Ig-HTS) on average 3.7 months prior to overt relapse/progression in 16 of 19 (84%) patients. It should be noted that imaging was done based on protocol-defined timepoints rather than based on clinically detected relapsed, therefore, the lead time is partly a function of the protocol driven timing of the imaging studies, however, several patients who ultimately relapsed has detectable ctDNA and negative imaging. The authors also note that some patients who were ctDNA-negative but imaging positive probably reflects the common occurrence of false-positives by imaging.

In addition, the presence of ctDNA was significantly associated with inferior PFS (P=0.033), increased risk of relapse (P=0.0006) and death (P=0.003). The authors conclude that the high sensitivity of ctDNA could allow for more judicious use of routine imaging, which is associated with high costs and radiation exposure.

In a recent review by Sriam et al., the authors note that traditional surveillance methods are currently used for clinical assessment and routine surveillance imaging, however, MRD refers to the detection of disease below the limit of these traditional surveillance methods. The authors argue that while no prospective trials to date have conclusively shown improved outcomes in patients undergoing imaging, may clinicians routinely use imaging in today’s clinical practice. The authors note that “given the risks cost ineffectiveness, false-positive results, and lack of clear impact on outcome, radiographic surveillance is not the ideal monitoring modality in lymphoma.” Due to this, other methods of disease burden assessment are needed.

The use of ctDNA and cellular DNA “as a monitoring strategy in lymphoma can aid in assessment of disease burden (MRD), as well as prognostication, customization of therapy (‘risk-adapted’ strategies), monitoring for relapse, and consideration of early intervention (‘preemptive’ strategies), while reducing radiation exposure from surveillance imaging modalities that are presently used.” In summary, the authors conclude that NGS MRD assessment is highly sensitive and specific, it can provide information on changing treatment, and could allow for a reduction or complete elimination of surveillance imaging.

CONCLUSION

In closing, we support the establishment of an LCD for MRD testing in cancer and thank the Noridian and the MolDX program for drafting a policy intended to keep pace with rapidly growing evidence on the importance of MRD testing to improving patient outcomes across many cancers. We hope that the comments provided in this letter will help to ensure a finalized policy that provides a sustainable evidence-based framework for coverage of high-quality MRD assays for Medicare beneficiaries with cancer.

Appendix 1: Comments related to DRAFT Local Coverage Article: Billing and Coding: MolDX: Minimal Residual Disease Testing for Cancer

As noted in our Draft LCD comments above, we support the continued coverage for NGS MRD testing in ALL, CLL, MM. The ICD-10s listed as “Group 1 Codes” within the “ICD-10 Codes that Support Medical Necessity” reflect these conditions appropriately, from our perspective.

  • MM: C90.00 through C90.02
  • ALL: C91.00 through C91.02
  • CLL: C91.10 through C91.12

We further request the inclusion of ICD-10 codes that reflect specific NHL conditions in this section, consistent with our Draft LCD comments above.

NHL

  • DLBCL: C83.30 through C83.39; C85.20, C85.22
  • MCL: C83.10 through C83.19
  • Other: C85.10, C85.18, C85.19; C85.80 through C85.99

Finally, we note that MRD assessment is relevant in other hematologic malignancies outside of the lymphoid space, such as AML and CML. While we do not have specific recommendations for relevant ICD-10 codes in these conditions, Noridian and MolDX should consider inclusion of codes that reflect these conditions as well.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

Additionally -

MolDX maintains that, while inclusion of MRD testing in established guidelines is considered as part of a coverage decision, it does not stand alone. The additional criteria set forth in the policy must also be observed for a positive local coverage decision. Additionally, we do not require that guidelines support the use of a specific technology for MRD testing. Therefore, we have not revised the wording of Coverage Criterion #3.

19

The following comment was submitted to Palmetto GBA and Noridian:

Please allow me to provide comments regarding the coverage for methods to detect minimal residual disease (MRD) in hematological malignancies, and later for the solid tumors. I have a career of greater than 20 years working in the field of myeloma, being involved in clinical care and research. I am a named Professor at the Mayo Clinic, and currently serve as the Interim Executive Director of the Mayo Clinic Cancer Center. I have a long career of academic productivity with an H index of 115 and close to 49,000 citations (November 2020). I provide this as background to document my expertise.

I have seen great improvements in my clinical practice (solely focused on myeloma) because of the addition of MRD determination to better understand prognosis and management of patients. Fortunately, many patients can achieve very deep responses (complete remission) and determination of MRD status has become an essential component of my practice. With its use I advise patients on their likely prognosis, and I also use it to better inform clinical decisions. While there is much to be learned still, we in myeloma have a long tradition of incorporating biomarkers to better monitor the disease. About 15 years ago we started using the serum free light chain assay, a new tool to monitor myeloma, and one without which I could not imagine a modern myeloma practice. In my opinion, the same is true for the incorporation of MRD determination.

Every single study where MRD has been tested, and two subsequent meta-analysis, have shown its value as a prognostic marker - this is beyond dispute. We now have the next generation sequencing assay (clonoSEQ®) approved by the FDA that allows determination of residual cells at a sensitivity of one cell per million. Hopefully, in the future MRD status will also be incorporated as a surrogate marker for drug development by regulatory agencies.

In my clinical practice I routinely use MRD determination in the post-transplant setting. In this setting it best informs about prognosis and for me allows me to decide on whether post stem cell transplant consolidation, or whether a second stem cell transplant should be considered. I also test for MRD as we make decisions about treatment continuation on patients who have long lasting complete responses. Patients often are placed on chronic maintenance therapy, most commonly with lenalidomide (Revlimid). This maintenance is associated with toxicities and comes at a significant cost (to the patient and payers). Over time patients carry the accumulated burden of that toxicity, and often want to, or have to stop therapy. To make a more informed decision I will test for MRD in their bone marrows. If a person is negative and they are on the brink of personally deciding to stop treatment (e.g., as a consequence of fatigue or diarrhea) they may have greater comfort in knowing they are MRD negative. Likewise, someone who is tolerating the treatment relatively well but remains MRD positive might be further encouraged to continue on therapy. It should be noted that MRD is never the sole determinant of the clinical decision, but it always makes our conversation more informed.

My enthusiasm for the use of MRD is driven by my ability to incorporate the information in clinical decision making. One often underappreciated aspect of MRD testing is that it is not a binomial result (positive versus negative), but rather one that provides amplitude in measurement, and thus can be used to better understand clinical trajectories (improvement versus progression).

It is my hope that in time my colleagues who deal with other tumors ultimately understand and benefit from a clinical practice that is better informed because of this type of testing. Additional work is being done to further validate MRD (and similar) testing in other B and T cell malignancies, but similar clinical tests are sorely needed for the solid tumors.

This opinion is solely mine, and not that of my employer or anyone else. I have worked closely with Adaptive Biotechnologies and have been compensated for those services, but that works does not affect what I present here. In my opinion, to have a simplified process for reimbursement for this test would alleviate any remaining concerns that patients might have.

I thank you in advance for your consideration.

Thank you for your thoughtful comments and support of this policy. Please refer to Responses 1-4 listed above for a discussion on the approach to reimbursement for MRD tests.

20

The following comment was submitted to Noridian:

I am writing to express my support for the proposed Local Coverage Determination (LCD) for Minimal Residual Disease Testing for Cancer.

In my tenure of 16 years as a PharmD, I have seen that many cancer patients on immunotherapy, specifically PD-1/PD-L1 inhibitors, fail to achieve a durable positive response. In addition, at present it is challenging to timely determine who may or may not respond to treatment.

Evidence from literature suggest the utility of existing predictive biomarkers, such as PD-L1 expression and tumor mutational burden can help determine patients’ eligibility to be initiated on immunotherapy, but they fail to determine patients’ response to treatment. Because of this, the current approach relies entirely on serial imaging, which can be costly and may at times be difficult to interpret because of pseudoprogression.

In addition, a growing body of literature exists around circulating tumor DNA as a biomarker that provides a much more real-time assessment for treatment monitoring compared to imaging. Given the above shortcomings, many patients on immunotherapies are treated beyond progression, which leads to unnecessary immune-related adverse events (irAEs) and increased costs to our health care system.

I therefore see a significant need for improved biomarkers to monitor the effectiveness of immunotherapy drugs. Based on the current literature, I believe that Signatera- a bespoke, tumor- informed circulating tumor DNA is a viable solution. Signatera performance has been clinically validated in multiple cancer types, and the most recent publication of Signatera in the Nature Cancer journal showed changes in ctDNA from baseline to two cycles of immunotherapy, predicted patient response better than any other currently used biomarkers.

I therefore write to you in strong support of the proposed LCD for the use of Signatera MRD test in patients with solid tumors being treated with immunotherapy. I feel that reimbursement in this space will play an instrumental role in improving treatment response monitoring, thus reducing unnecessary financial costs and potential toxicities associated with overtreatment.

Thank you for your thoughtful comments and support of this policy.

21

The following comment was submitted to Noridian:

We applaud MolDX’s action with the proposed local coverage decision for MRD testing. We believe this LCD appropriately reflects the clinical utility of immunotherapy response monitoring across solid tumors, as well as the strong potential for future validation and implementation of personalized MRD testing in additional clinical indications.

We would like to propose several edits, which can help clarify the coverage criteria and improve access for Medicare patients to reasonable and necessary MRD testing in the future:

Criterion #6: Can MolDX please clarify that “explicit therapy indicated” refers to a class of therapies, not a particular therapeutic agent. Examples of therapeutic classes are immune checkpoint inhibitors, PARP inhibitors, CDK4/6 inhibitors, tyrosine kinase inhibitors, chemotherapy, etc.

Criterion #7: Can MolDX please clarify that “test performance must be comparable” refers to clinical test sensitivity and specificity, and that this clinical performance must be demonstrated in each intended use population where the test provider seeks coverage.

Criterion #8: Can MolDX please clarify that for a test to gain coverage under this LCD, there should be peer-reviewed, published evidence of clinical test performance in each intended use clinical population where the test provider seeks coverage. This should include serial specimen collection and long-term patient outcome determination over a clinically meaningful period of time, to ensure that the test performs reliably in serial use, and to ensure that patient outcomes are appropriately ascertained.

We look forward to working with Medicare and with the oncology community, to ensure that MRD testing is implemented fairly and equitably, with strong validation data that brings confidence to patients and physicians.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

22

The following comment was submitted to Palmetto GBA:

I am a Medical Oncologist and the Medical Director at Austin Cancer Center in Austin, TX. I have been a practicing oncologist for 7 years, during which I have participated in multiple clinical trials for solid tumors and specialize in thoracic, head & neck and GI malignancies.

Check point inhibitors (CPIs) ushered in a new era of immunotherapy for oncology patients. These new agents give many solid tumor patients a treatment option that could significantly prolong their life. Even with the progress made, we still face significant challenges in predicting which patients will respond and have durable responses to CPIs. To complicate matters further, CPIs have a very distinct phenomenon not seen with traditional chemotherapy known as pseudo-progression (immune flare).

Currently, common practice is to continue CPIs if the first restaging scan is showing stable-to-mild progression of the disease. The hope is that any progression is pseudo-progression and will shrink on subsequent imaging. Even PET scans can be ambiguous as the immune flare from CPIs can cause high FDG uptake. This results in patients receiving futile treatment, increased risk of toxicities from continued CPIs use and increased radiation exposure from frequent imaging, in addition to delaying other potential therapies. A patient population that is susceptible to significant mortality and morbidity during treatment with CPIs are head and neck cancer patients with significant local disease and equivocal findings on imaging. These patients commonly have local symptoms, potential airway compromise and threatened invasion into surrounding major blood vessels. Considering these tumors are present in a small anatomical area, we don’t always have the luxury on continuing CPIs and following their imaging for 2-3 months as the results could be catastrophic. We need a faster, more reliable method to distinguish pseudo-progression from non-responders.

Signatera’s bespoke liquid biopsy is designed to detect changes in the tumor burden on a molecular level that is highly specific to a patient’s tumor. It has already received the FDA’s breakthrough technology designation.

Multiple peer-reviewed articles have shown the utility of ctDNA in differentiating between true progression and pseudo-progression. A recent paper in Nature by Bratman et. al. showed that Signatera, in conjunction with radiological assessment has a 100% positive predictive value (PPV) in identifying non-responders. Patients who had molecular progression based on the Signatera test had an objective response rate (ORR) was zero percent (0%) and the 6-month progression free survival (PFS) was zero as well.

I would strongly advocate for reimbursement of Signatera ctDNA monitoring for patients treated with immunotherapy. This will give us a much more accurate method of detecting disease progression earlier, prevent futile CPIs administration, prevent delay in other treatment options, decrease radiation exposure from repeated imaging and ultimately decrease the total medical cost of those. I believe this technology is paradigm shifting and will have far reaching implications in personalized cancer care and clinical trials in the future.

Thank you for your thoughtful comments and support of this policy.

23

The following comment was submitted to Palmetto GBA:

The Colorectal Cancer Alliance is largest patient advocacy organization dedicated to the colorectal cancer prevention, research, and supporting patients and their families. We are writing to express our support for the proposed Local Coverage Determination (LCD) titled: MOLDX, Minimal Residual Disease Testing for Cancer.

The Alliance believes that for patients to have optimal clinical outcomes, Medicare should cover all proven effective testing and treatment options. There is clear evidence that Minimal Residual Disease testing (MRD) may be an improvement over current surveillance methods in detecting or predicting recurrent colorectal cancer. MRD may also help risk-strategy patients to determine whether or not they may benefit from adoptive cellular therapy (ACT).

We appreciate that CMS is proposing to provide coverage for MRD. Absent coverage, tools that may improve clinical outcomes may not be employed given costs consideration and we support the proposed LCD to ensure that MRD is available so that testing drives clinical decisions rather than relying on physician discretion.

We look forward to CMS finalizing the proposed LCD. Please feel free to contact me if you have any questions about our support of the LCD or the Alliance in general.

Thank you for your thoughtful comments and support of this policy.

24

The following comment was submitted to Palmetto GBA:

We are writing as hematologists and medical oncologists at Stanford Cancer Center and at the National Cancer Institute (NCI) at the National Institutes of Health, and we both share a clinical interest in use of MRD in lymphomas. We were excited to learn about this new Draft LCD, especially when considering its foundational nature for use of various MRD tests for early detection of clinically relevant disease progression in patients with diverse cancers.

We were encouraged to read about the broad scope of the diseases envisioned in the Proposed/Draft LCD document including solid tumors and hematological malignancies. However, we were surprised to see that lymphomas were not included in this summary, despite the evidence level for the significant prognostic importance of MRD in several B-cell lymphomas.

Separately, while the LCD addresses MRD for cancer monitoring using ctDNA for solid tumors, it seems to overlook use of ctDNA MRD for hematological cancers using acellular blood plasma or serum. In fact, the cited data for use of clonoSEQ® for MRD in myeloma and ALL have not used ctDNA. Instead, these studies have essentially entirely relied on cellular bone marrow aspirates, not peripheral blood, and in CLL the assayed compartment has been cellular, not cell-free ctDNA. Therefore, opportunities to noninvasively detect MRD in the blood of patients with hematological malignancies using existing methods seem poorly captured in this proposed/draft LCD.

Finally, the description of the MRD techniques for hematological malignancies in the current document seems skewed to clonoSEQ®, without adequate consideration of alternative assays in the spirit of a foundational LCD. This LCD doesn’t consider alternative NGS techniques for lymphoma MRD testing such as CAPP-Seq/AVENIO, PhasED-Seq, and other LDT offerings from CLIA labs.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

25

The following comment was submitted to Palmetto GBA:

On behalf of Cadex Genomics we appreciate the opportunity to comment on Proposed Local Coverage Determination. We applaud the recognition of the utility of blood based diagnostic testing for monitoring therapeutic response and would like to provide the following comment.

Regarding coverage indications, limitations, and/or medical necessity item # 6: If the test is to be used for monitoring therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit therapy indicated.

The current standard of care for monitoring therapeutic response is radiographic evidence of response or progression. Radiographic evidence of tumor response is determined by changes in tumor size, and it is independent of therapy type. Tests which can monitor therapeutic response as measured by changes in cfDNA or ctDNA can also predict progression regardless of therapy type as changes in tumor-derived cfDNA (ctDNA) reflect tumor burden and do not depend on the specific type of therapy used.

We therefore suggest, that a test that demonstrates clinical validity of its results in published literature for therapy response monitoring with comparable or better performance to radiographic imaging should not be limited to an explicit therapy type as this could deprive patients from a clinically useful assessment of tumor response if different therapeutic strategies are used.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

26

The following comment was submitted to Palmetto GBA:

The Personalized Medicine Coalition (PMC), a multi-stakeholder group comprising more than 200 institutions across the health care spectrum, appreciates the opportunity to comment on the MolDX Proposed Local Coverage Determination (LCD) for Minimal Residual Disease (MRD) Testing for Cancer. Because of its importance in informing the delivery of personalized medicine, PMC supports the LCD process moving forward for MRD testing of hematologic malignancies and solid tumors in patients with a personal history of cancer. We are concerned, however, that the proposed LCD may unintentionally impact patient access to clinically relevant MRD testing now and in the future without further discussion on testing limits established by the Centers for Medicaid and Medicare Services’ (CMS’) National Coverage Determination (NCD) on Next Generation Sequencing (NGS) for Medicare Beneficiaries with Advanced Cancer before issuing a final LCD.

Personalized medicine is an evolving field that uses diagnostic tools to identify specific biological markers, often genetic, to help determine which medical treatments and procedures will be best for each patient. By combining this information with an individual’s medical history, circumstances, and values, personalized medicine allows doctors and patients to develop targeted prevention and treatment plans.

Personalized medicine is helping to shift the patient and provider experience away from trial-and-error and toward a more streamlined process for making clinical decisions, which will lead to improved patient outcomes, a reduction in unnecessary treatment costs, and better patient and provider satisfaction. PMC’s members are leading the way in personalized medicine and recommend that patients who may benefit from this approach undergo appropriate testing and tailored treatment as soon as possible during their clinical experiences.

Statement of Neutrality

Many of PMC’s members will present their own responses on the proposed LCD and will actively advocate for those positions. PMC’s comments are designed to provide feedback so that the general concept of personalized medicine can advance, and are not intended to impact adversely the ability of individual PMC members, alone or in combination, to pursue separate comments with respect to the MolDX proposed LCD for MRD testing for cancer or related issues.

Support for Coverage of MRD Testing and Considerations for Repeat Testing

As recognized in the proposed LCD, MRD testing can help determine critical aspects of care for patients with chronic lymphocytic leukemia, multiple myeloma, acute lymphoblastic leukemia, colorectal cancer, lung cancer, breast cancer, bladder cancer, esophageal cancer, and others. MRD testing is an increasingly important tool used by physicians to predict long-term patient outcomes, to gauge treatment response, to stratify patient risk and to assess signs of remission or relapse. To ensure that patients and providers can continue to receive these benefits, PMC highlighted issues related to NGS-based MRD testing in comments as CMS developed and refined its NCD on NGS for Medicare beneficiaries with cancer.

MRD testing is guideline-driven and, by definition, is an assessment that is performed more than once during a patient’s management. MRD assessment is a series of tests used for purposes beyond a patient’s primary diagnosis. PMC believed that CMS’ initial proposal limiting an NCD to a single test at the point of a patient’s diagnosis with advanced cancer was problematic because evidence was mounting that established the value of using NGS-based MRD tests that are conducted multiple times in the course of a patient’s care.

In our comments to CMS in 2018, we noted that by proposing to limit coverage for an NGS-based test in instances where a patient had “either not been previously tested using the same NGS test for the same primary diagnosis of cancer, or for repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physiciani” the NCD would be too restrictive to support clinical testing services like MRD. We raised the single test limit issue again when the NCD was under revision in 2019.

The language published in the final NCD was revised to state that coverage would be provided if a patient had “not been previously tested with the same test using NGS for the same cancer genetic content.” This change is an improvement from the original NCD language, as it appears to be intended to block duplicative NGS testing while allowing repeated use of a test when there is an expectation for different cancer genetic content. We believe this revised language can be appropriately applied to NGS MRD testing to allow coverage of serial MRD tests.

We believe that the draft LCD presumes the NCD limits the ability of contractors to cover more than one MRD test in a patient with cancer, and therefore proposes an approach for MRD serial testing where the initial baseline test and subsequent assays together comprise a single test. While this policy allows multiple assessments (which we strongly agree must be covered to provide appropriate care for patients, per guidelines and clinical practice), PMC does not believe this definition of MRD testing is necessary given the new language of the revised NCD.

In light of the crucial benefits MRD testing provides for patients and providers, we urge further discussion with CMS and stakeholders on flexibility of testing limits under the NCD, before finalizing this LCD. In particular, we urge you to seek clarification from CMS with the goal that CMS will allow MolDx to use a much less complicated approach for coverage of MRD testing in the final LCD. The final LCD should convey a more rational framework for coverage of MRD testing. This will lead to simpler and more transparent coding and pricing for all stakeholders. We fear that not doing so will impede Medicare beneficiary access and lead to suboptimal care for some patients.

Conclusion

Thank you for your work on the proposed LCD and for considering our comments.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

27

The following comment was submitted to Palmetto GBA:

I have incorporated the Signatera circulating tumor DNA assay into my medical oncology practice, and I am writing in support of Medicare coverage for this assay for the detection of molecular residual disease, surveillance, and treatment response monitoring.

As a practicing oncologist, my goal is to provide patients with the best evidence-based management of their cancer. I strongly feel circulating tumor DNA represents a technology that will transform our management of patients with a variety of solid tumors, and have experienced this personally with the use of the Signatera assay in my patients.

In terms immunotherapy, early and accurate assessment of response to treatment is vital to maximizing patient outcomes while limiting the financial burden imposed by these very expensive treatments. It is therefore necessary to adopt tools that accurately gauge patient responses to therapy into routine practice. I feel the use of the Signatera assay in my practice has improved my ability to monitor patient responses to therapy, thereby allowing for earlier and more informed treatment decision making.

As an example of this clinical utility, I recently used the assay in a patient who has high grade urothelial cancer to determine whether chemotherapy was needed after surgery.

The utility of the Signatera assay in patients on immunotherapy has been demonstrated in the literature as well. Data recently published by Bratman et al. in Nature Cancer demonstrated that the Signatera assay was able to accurately predict responses to PD-1 inhibition when measured at baseline and at cycle 3 day 1 (Bratm an, et al. 2020). The ability to non-invasively predict responses to immunotherapy agents this early in treatment will allow us to identify those patients who will benefit from changes to the therapy plan, thereby saving non-responding patients precious time, while limiting unnecessary side effects and healthcare costs.

Additionally, I have entered into multiple research Initiatives with Natera further utilizing the use of the assay in patients with both SCLC and NSCLC, to include patients receiving immunotherapy.

In summary, I feel that ctDNA monitoring will soon be guideline directed standard of care in the treatment of patients with a variety of solid tumors. I am happy to lend support to the Medicare coverage of this testing for the detection of molecular residual disease, surveillance, and treatment response monitoring.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

28

The following comment was submitted to Palmetto GBA:

I would like to comment on the following document MolDX: Minimal Residual Disease Testing for Cancer.

I am a GI Medical Oncologist at Duke University and the Co-Leader of the Duke Molecular Tumor Board. I am supportive of Medicare allowing access to minimal residual disease (MRD) testing for patients with resected cancers. MRD testing is a new and innovative mechanism to more accurately identify patients who will recur and enable better treatment options to extend overall survival. In some cases, negative MRD test results could allow us to de-intensify surveillance and reassure patients. I believe that the draft policy will help us bring this important technology to our clinics.

In general, I believe that the use cases in the coverage policy are aligned with current clinical practice, however I don’t agree with the bullet point which requires the use of an MRD test to preclude all other testing for a patient. The patients that I treat present with a variety of different conditions and comorbidities that may require a variety of different diagnostic tests. Additionally, since MRD testing is new, we will want to preserve access to other complementary assays. Orthogonal testing provides greater confidence in our test results and allows us to build medically appropriate survivorship plans. As a result, I don’t think it is appropriate to preclude all other monitoring tests when a MRD test is employed. As a treating physician, I ask that I be trusted to practice medicine in a manner that gives my patients the best outcomes possible.

While there are scenarios where it is not medically necessary or appropriate to run redundant or overlapping tests, there are situations where equivocal or confusing results demand alternate testing approaches. For this reason, I believe it is appropriate to amend the coverage policy to only restrict the use of multiple MRD tests on the same patient.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

29

The following comment was submitted to Palmetto GBA:

Thank you for the opportunity to submit comments on the proposed LCD: MolDX: Minimal Residual Disease Testing for Cancer. Exact Sciences Corporation is a molecular diagnostics company working to deliver life-changing innovations through earlier detection and smarter answers for patients. We are the manufacturer of the Cologuard® and Oncotype DX® tests with four CLIA and CAP certified labs in three locations across the United States. We also recently announced an agreement to acquire Thrive Earlier Detection Corp., developer of CancerSEEK, a blood-based test for detecting multiple types of cancer at earlier stages. That acquisition is expected to close in the first quarter of 2021 pending satisfaction of closing conditions and receipt of required regulatory approvals.

Exact Sciences commends Palmetto GBA for the proposed LCD and supports coverage for minimal residual disease (MRD) testing for Medicare beneficiaries with a personal history of cancer. We agree that MRD testing has demonstrated a significant impact on cancer diagnosis and treatment and support facilitating beneficiary access to such testing.

With respect to the eight coverage criteria specified in the proposed LCD, Exact Sciences offers the following comments regarding four of the eight criteria :

Recommended Modifications to Text of Proposed LCD

The test is demonstrated to identify molecular recurrence or progression before there is clinical or radiographical evidence (per the standard-of-care for that specific tumor type) of recurrence or progression; and demonstrates sensitivity and/or specificity of subsequent recurrence or progression comparable with radiographical evidence of recurrence or progression or, when used in conjunction with imaging, improves upon the sensitivity and/or specificity of subsequent recurrence or progression.

Exact Sciences believes that the ability to compare sensitivity, specificity, and other test characteristics across modalities, especially decentralized radiographic and nuclear medicine approaches, may pose challenges to practical implementation of the policy. Therefore, we recommend replacing comparability of sensitivity and specificity with the ability of any modality to direct a meaningful clinical outcome.

The test, alone or adjunct, is demonstrated to identify recurrence or progression with sensitivity and specificity that is at least comparable to other established, standard-of-care (non-MRD) forms of surveillance or monitoring, if they are available for a given tumor type.

We reiterate our comment above and encourage Palmetto GBA to replace comparability of sensitivity and specificity with the ability of any modality to direct a meaningful clinical outcome.

The proposed criterion would establish a vague standard of “considerably more accurate,” which would create interpretive challenges for stakeholders and leave them guessing as to how Palmetto GBA would apply it. Furthermore, surveillance monitoring is only used for certain tumor types (e.g., liver, colon, pancreatic, ovarian cancer), which makes this standard difficult to apply to other tumor types that may still benefit from MRD testing but do not have a comparator surveillance test (e.g., lung cancer).

We urge Palmetto GBA to not limit coverage to only those MRD tests that preclude other surveillance or monitoring tests. When added to current surveillance regimens, MRD testing may greatly improve the ability to identify recurrence at an earlier time point.

If a class of test is to be used for monitoring therapeutic response, it must demonstrate the clinical validity of its results in published literature for the explicit therapeutic area indicated.

As written, we believe this criterion would be read to require every MRD test to produce published data on test validity for every branded drug in a class. Our recommended modifications are intended to clarify that if MRD testing has proven to be clinically impactful in a therapeutic area, then other MRD tests with the same performance (sensitivity & specificity) should not have to demonstrate validity against that therapy.

If similar MRD tests exist in the market and are covered by this contractor, test performance for the test must be comparable to existing tests.

In addition, Exact Sciences offers comments on the following section from the LCD:

“MRD testing often requires two types of assays to be performed as part of the service. First, a sample is taken from tumor diagnostic material to establish a baseline tumor signature as defined by the test methodology. This is followed by a series of assays run on blood to detect the presence or recurrence of tumor based on the measured biomarkers, expression, or other analytes over various timepoints. This series of assays comprises a single test when the patient is known to have cancer. When the patient is NOT known to have cancer (specifically when there is no clinical, radiographical, or other biological evidence that tumor cells remain post treatment and subsequently the patient is no longer being subjected to therapeutic interventions for cancer), a second kind of test may exist wherein a single additional timepoint may constitute a single test.”

The above section from the LCD seems to infer that the final National Coverage Determination (90.2) for next-generation sequencing limits coverage to one MRD test for a patient and, as written, creates a complicated description of coverage that may not be warranted.

We agree that MRD testing is generally performed more than once to guide patient management and may often be run serially. However, in our understanding of the language, NCD 90.2 does not block duplicative testing. The text states testing would be covered in a patient who has not “not been previously tested with the same test using NGS for the same cancer genetic content.” We believe that MRD testing by NGS assesses the presence and quantity of clonal signatures, which change over time relative to treatment. Thus, it is not the same genetic content and therefore, does not represent duplicative testing.

We urge you to seek guidance from CMS to clarify this section so that coverage of serial MRD testing remains in place as proposed and to maintain alignment with the guidance on repeat testing from NCD 90.2.

Thank you for considering our comments.

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

We have addressed your comments in Responses 1-4 listed above.

30

The following comment was submitted to Palmetto GBA:

I am writing in support of Medicare coverage for the Signatera circulating tumor DNA assay, developed by Natera. I have considerable experience working with Natera, and have found this company to be a leading enterprise within the ctDNA space, focused on improving patient outcomes through their circulating tumor DNA technology. To this end, I have been actively collaborating on multiple research initiatives with Natera, and have employed this technology in my own clinical practice, where I have found the information the test provides a considerable benefit to my treatment decision making. We are also actively integrating this technology into clinical trials that are now open at our institution. As an example, we have presented and published on the experience and value of using this circulating tumor DNA technology at the leading conferences (American Society of Clinical Oncology – ASCO 2020, European Society of Medical Oncology – ESMO 2020 as well as the Society of Immunotherapy for Cancer – SITC 2020). Based on my research and expertise, I was invited by the ASCO to write an editorial at ASCO Daily News that was just published in October 2020 supporting the serial use of circulating tumor DNA assays to assess treatment response in patients receiving immunotherapy.

It is clear that better tools for treatment response monitoring in patients on immunotherapy are needed. Our current modalities for discerning which patients are responding to treatment with these agents are insufficient. Recent data suggests that over half of patients who demonstrate stable disease on their first imaging study while on immunotherapy do not experience a durable clinical benefit (Nabet et al., 2020). This is turn leads to many patients who are unnecessarily treated with agents associated with high costs and potentially serious side effects.

Natera recently published data in partnership with the Princess Margaret Cancer Centre demonstrating that the Signatera assay is sensitive and prognostic in patients with a variety of advanced solid tumors, as well as predictive for responses to immunotherapy when measured early on-treatment. This represents a potential paradigm shifting advance that offers advanced cancer patients and clinicians the opportunity to better select patients for continuation of therapy or conversely, alternative approaches to treatment.

Last few months, multiple articles and research published in leading journals is supporting the feasibility of such an approach including work from our group.

The importance of early response monitoring in patients on immunotherapy cannot be overstated. I am happy to support the Medicare coverage of this test across multiple cancer types, and I am happy to provide any additional insights that may be helpful.

Non-invasive monitoring in patients receiving immunotherapy would be of great value for a variety of patients with different malignancies. It would decrease toxicity and provide rationale for escalation in the right patient. Furthermore, such an approach would be very cost effective since the cost of a single dose of immunotherapy (pembrolizumab for example is almost $~48,000 for a single dose).

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

31

The following comment was submitted to Palmetto GBA:

I am a practicing oncologist at the University of Louisville. I regularly see patients with both early­ stage and advanced-stage disease. My clinical experience and my review of the recent literature leads me to believe that tumor informed MRD testing can be very useful to support better treatment decision-making and patient counseling across a variety of histologies and clinical scenarios. Therefore, I am writing in support of the proposed coverage policy published by MolDX.

In my own practice I have used Signatera MRD test in multiple patients, mostly in the context of Colorectal and other GI cancers, and I find that it provides useful information that is easy to interpret for my patients and my staff. Patients who are MRD-positive clearly need additional treatment, intervention, or more intensive diagnostic scans. I believe this tool can be applied pan-cancer, though its utility may be more pronounced in certain scenarios where the subsequent clinical action is already made clear.

New data reported by Bratman, et al indicate that tumor informed ctDNA can be immediately useful for monitoring and predicting response to immunotherapy across a range of cancer types. This can really be a paradigm shift in how we treat patients with immune checkpoint inhibitors. Current biomarkers are not very predictive of response to ICI, and the CT scans can often be hard to interpret due to phenomena like pseudo-progression. This leads many patients to stay on treatment too long, foregoing the opportunity to switch earlier to potentially more effective therapy options, including new combination approaches.

Conversely there are patients who have durable clinical responses and ask when they can discontinue treatment, a question for which oncology societies still do not provide clear guidelines.

In particular, I had one patient recently where the Signatera test was helpful in resolving such a question with regards to appropriate treatment discontinuation. This is patient with extensive medical problems who had been on chemotherapy for metastatic colon cancer for several years with good response but became severely anemic in April 2020 requiring hospitalization. The patient subsequently improved and was discharged but was quite debilitated when seen in clinic to restart chemotherapy. Due to this we were inclined to delay or even stop chemotherapy, but the patient was very anxious about the possibility of cancer progression. Since ctDNA had just become available, we chose to test the patient to see if they may be MRD negative in which case, treatment discontinuation would be reasonable, and they too would be more comfortable with the decision. Fortunately, the patient’s ctDNA test did show to be MRD negative and so we did not restart chemotherapy. Patient has since had two more ctDNA tests over the last seven months and both have been negative. After being able to discontinue chemotherapy, the patient’s overall condition and performance status has improved, and reports a better quality of life. I believe that the availability of MRD testing was instrumental in helping make a clinical decision about treatment discontinuation in this case which would have been very challenging to do with conventional modalities.

In closing, I believe tumor informed MRD testing will become part of standard care across most solid tumor histologies, and I applaud Medicare's effort to provide coverage for its routine use

References were provided for review.

Thank you for your thoughtful comments and support of this policy.

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The following comment was submitted to Palmetto GBA:

I am a medical oncologist affiliated with the University of Texas, MD Anderson Cancer Center. I have been a practicing physician for 11 years and 5 months.

As a general oncologist, I treat patients with various tumor types where immunotherapy is indicated and I frequently encounter clinical scenarios where I can recommend chemotherapy, immunotherapy, or a combination of both. Immunotherapy has clearly been a significant advancement in the treatment of many solid tumors for the benefit of many of our patients as they have demonstrated results towards improved quality of life, progression free survival, and overall survival. However, the clinical challenge of pseudoprogression is clearly a real one. Decisions to continue or discontinue immunotherapy are frequently very difficult. The difference between continuing immunotherapy in the setting of true progression and declining performance status or discontinuing immunotherapy in the setting of pseudoprogression and effective therapy can translate to patient harm. Furthermore, while immunotherapy is now the preferred first line standard of care for various tumor types, clinical studies have demonstrated a higher progression free survival and mortality with immunotherapy as compared with chemotherapy.

Allowing for non-invasive MRD detection in patients with solid cancers treated with immunotherapy represents a critical tool in personalized medicine. Molecular analysis of circulating tumor DNA (ctDNA) offers a minimally-invasive method to assess response to therapy or lack of benefit. This is even more relevant in an underserved/underinsured population where costs/time commitments to scans can be significant due to limited income.

Tumor-informed ctDNA custom-built assays represents a reliable and validated methodology for accurate MRD detection through ctDNA analysis in patient with CRC. The personalized mPCR-NGS platform is an innovative tool that provides clinicians with a reliable, sensitive, specific, and dynamic detection of molecular disease burden.

As illustrated in Bratment et al., Tumor-informed ctDNA custom-built assay was designed in 98% of cases analyzed and proved usefull in therapy monitoring where increase in ctDNA identified patients who did not benefit from continuation of pembrolizumab whereas patients who had a decrease in ctDNA experienced a better outcome. Furthermore, clearance of ctDNA after pembrolizumab administration identified a group of patients with exceptional outcome.

I feel that reimbursement of Signatera for patients with advanced solid cancer and treated with immunotherapy is warranted given the published data, especially where such results are felt to be useful in guiding treatment decision making. This remains an area of great unmet clinical need for the Medicare population, where imaging results can be challenging to interpret, toxicities can be great, and costs can be prohibitive.

As a physician-scientist, I am committed to improving outcomes for my patients through the integration of technological advancements into clinical practice. I strongly believe that Signatera’s personalized approach for MRD detection holds significant promise to usher in a new era of personalized medicine with implications for improving the clinical management of patients treated with immunotherapy.

Thank you for your thoughtful comments and support of this policy.

 

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Associated Documents

Medicare BPM Ch 15.50.2 SAD Determinations
Medicare BPM Ch 15.50.2
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