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

I am writing to support your proposed LCD for Signatera in stage 2-3 CRC. I am Director of GI Cancer Research at West Cancer Center. I had previously worked at Mayo Clinic Rochester for 15 years. I am also co-chairing the CTEP/ NCI GI Steering Committee, but I want to point out that the opinion regarding the clinical utility of Signatera is my own and does not represent the opinion of NCI or CTEP in any way.

Based on the recently published data in JAMA Oncology, I believe the Signatera test has strong clinical utility for the two use cases described in the draft LCD, offering the opportunity to potentially de-escalate adjuvant treatment for those patients who are MRD-negative and in MRD-positive patients to escalate treatment approaches in situations where by just clinical judgment and traditional staging no adjuvant chemotherapy would be administered. I plan to use the test this way in my own medical practice.

Please feel free to contact me for any questions or queries you might have.

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

As a medical oncologist and director of Medical Affairs at the NSABP Foundation, I am writing to express my support for Natera's Signatera tests that provides clinicians with an invaluable tool for sensitive, specific, and dynamic detection of molecular disease burden. Prospectively collected and retrospectively analyzed clinical studies with Signatera support its clinical utility in a range of applications including improved staging at diagnosis, post-surgical risk stratification, therapy monitoring, and early relapse detection. The NSABP Foundation has been particularly focused on the findings in colon cancer. Here, there is an accumulation of evidence that clinicians will be able inform patient of potential risk of recurrence after surgery, after completion of standard adjuvant chemotherapy and monitor for early evidence of recurrence. We believe this technology will change the way that clinical care is delivered and clinical trials are conducted as well as facilitating to cost-effective drug discovery.

Currently patients with early stage colorectal cancer are treated on the basis of the pathologic findings at surgery. We know that only a small minority of patients actually benefit from expensive, toxic and inconvenient therapy. The ctDNA technologies we believe will clarity the patients who may benefit from therapy and also modify therapy based on monitoring. This should be an enormous benefit to our patients.

In conclusion, I support the draft LCD in its current form. We believe that tumor-informed and personalized ctDNA monitoring represents a great advance in the management of early stage CRC. This remains a dynamic and fast moving field. The NSABP and our investigators are excited to work to participate in conducting the next generation clinical studies to further advance this field.

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

I am writing to support your proposed LCD for Signatera in patients with Stage II to III colorectal cancer. I am a board-certified medical oncologist who has been in practice for 8 years, and specializes in the treatment of patients with gastrointestinal cancers. Colorectal cancers are one of the most common cancers diagnosed and treated in the US. For our patients with early stage colorectal cancer, we currently utilize clinical and pathological features of their tumor to determine risk of recurrence, and help us determine surveillance and adjuvant treatment strategies. However, we are in desperate need for more accurate measures of risk stratification, disease response to adjuvant therapy, and disease recurrence.

Molecular analysis of circulating tumor DNA (ctDNA) for patients after surgical resection of their primary colorectal cancer would allow us to determine if patients have evidence of residual disease. This would guide our recommendations for adjuvant chemotherapy, as we often do not know whether Stage II patients truly benefit from adjuvant chemotherapy. Serial monitoring of ctDNA after adjuvant chemotherapy could pick up early disease recurrence with rising ctDNA levels. In a disease like colorectal cancer where surgical resection or other localized therapies such as radiofrequency ablation or radiation therapy are good option for patients with oligometastatic disease, early detection could prolong patient survival and improve quality of life.

Based on the publication by Reinert et al (JAMA Oncology, 2019), I believe the Signatera test has strong clinical utility for the two use cases described in the draft LCD, offering the opportunity to deescalate adjuvant treatment for those patients who are minimal residual disease (MRD)-negative and to catch more recurrences early when there is stronger potential for curative surgery and treatment.

Please let me know if there are any further questions.

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

I am a medical oncologist affiliated the Beverly Hills Cancer Center. I have been a practicing physician for fifteen years and specialize in the treatment of patients with colorectal cancer (CRC), a cancer type that represents a significant health burden in the United Stat es, especially in the patients covered by Medicare.

Despite improvements in early detection leading to increased number of patients being diagnosed at a local and regionally advanced stage, distant disease relapse after surgery remains an area of great unmet clinical needs. The ability to detect patients at high risk for disease recurrence following curative surgery/ adjuvant chemotherapy is crucial for improving adjuvant treatment and surveillance strategies. Despite significant improvements in personalized medicine for metastatic CRC, local regionally advanced CRC continues to be treated according to guidelines initially developed over 20 years ago. Molecular analysis of circulating tumor DNA (ctDNA) offers a minimally invasive method to assess the prognostic outlook, response to therapy and risk of relapse in patients with cancer. Specifically in patients with CRC, the use of ctDNA to detect minimal residual disease (MRD) can facilitate risk stratification of patients that could aid in effective clinical decision-making.

I'm excited to support the current Medicare draft LCD fo r Signatera for adjuvant risk stratification in stage II and Il l colon and stage IIA rectal patients as well as surveillance in Stage II/ Ill CRC patients. I view this coverage decision as major step forward in opening up personalized medicine techniques for the first time to the management of early stage CRC. Specifically in patients with CRC, the use of ctDNA to detect minimal residual disease (MRD) can facilitate risk stratification of patients that could aid in effective clinical decision making. Signatera's custom-built test represents a reliable and validated methodology for accurate MRD detection through ctDNA analysis in patient breakthrough technology (as recently highlighted by FDA breakthrough status designation) that provide clinicians with an invaluable tool for sensitive, specific, and dynamic detection of molecular burden.

The clinical utility of signatera is support by several studies that successfully utilize the test for a range of applications including post-surgical risk stratification, therapy monitoring, and early relapse detection in different solid tumors. The clinical prospects of Signatera are also reflected by the growing list of prospective outcomes studies that use Signatera' s MRD detection at important clinical decision time points. I feel that reimbursement of Signatera for local and regionally advanced CRC is warranted given the published data, especially where such results are felt to be need for the Medicare population, where the toxicity of adjuvant chemotherapy is typically higher than younger and fit CRC n on- Medicare populations.

Please feel to contact me for any questions or queries you might have.

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

I am writing to support your proposed LCD for Signatera in stage 2-3 CRC. I am a board-certified medical oncologist based at Holy Cross Hospital Fort Lauderdale, Florida. Based on the published data in JAMA Oncology, I believe the Signatera test has strong clinical utility for the two use cases described in the draft LCD, offering the opportunity to deescalate adjuvant treatment for those patients who are MRD-negative and to catch more recurrences early when there is stronger potential for curative surgery. I plan to use the test this way in my colorectal cancer patients.

Please feel free to contact me for any questions or queries you might have.

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

I am writing to support your proposed LCD for Signatera in stage 2-3 CRC. I am a board-certified medical oncologist based at Moffitt Cancer Center. Based on the published data in JAMA Oncology, I believe the Signatera test has strong clinical utility for the two use cases described in the draft LCD, offering the opportunity to deescalate adjuvant treatment for those patients who are MRD-negative and to catch more recurrences early when there is stronger potential for curative surgery. I plan to use the test this way in my own medical practice.

Please feel free to contact me for any questions or queries you might have.

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

I am a medical oncologist affiliated with Mayo Clinic and have been in practice for about 4 ½ years. I practice exclusively gastrointestinal oncology and the majority of my patients have colorectal cancer (CRC), the third leading cause of cancer related deaths in the US.

Despite improvements in early detection, with methods such as colonoscopy, approximately 50% of patients with newly diagnosed colorectal cancer will develop metastatic disease. The ability to detect patients at high risk for disease recurrence following curative surgery is crucial for optimizing adjuvant treatment and surveillance. Detection of circulating tumor DNA (ctDNA) offers a minimally-invasive method to help assess response to therapy and determine risk of relapse in patients with cancer.

Specifically, in patients with CRC, the use of ctDNA to detect minimal residual disease (MRD) can facilitate risk stratification of patients that could aid in more effective clinical decision-making.

Based on the JAMA Oncology paper highlighting feasibility and utility of this technology I would like to offer my support to the current Medicare draft LCD for Signatera in the use of adjuvant risk stratification and surveillance of stage II and III colorectal cancer. The use of ctDNA to detect minimal residual disease (MRD) can facilitate risk stratification of patients that could aid in effective clinical decision- making. For example we know that up to 15% of patients with stage II colon cancer will relapse. We also know that all stage II colon cancers are not equal. The data suggests that the absolute benefit of fluoropyrimidine chemotherapy is 2-3%. Clearly there is a group of patients with “high risk” colon cancer that could have more of a benefit from chemotherapy. To date we have done a poor job of defining this “high risk” group. The Signatera assay better defines this “high risk” group.

I feel that reimbursement of Signatera for local and regionally advanced CRC is warranted given the published data. I plan on using Signatrera in my practice for the indications as discussed above.

Please feel free to contact me for any questions or queries you might have.

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

I'm writing in support of the draft LCD as currently proposed by Palmetto GBA / MOLDx for coverage of Signatera circulating tumor DNA (ctDNA) assay in Stage II and III CRC. As a board certified medical oncologist, I see a clear need for such testing to improve how patients with cancer are managed. In my experience with the assay, I've found it helpful in informing my management decisions.

I feel this assay addresses the currently significant clinical need for better identification of patients with local or regionally advanced CRC that may benefit from either treatment escalation or de- escalation. There is a current limitation of existing methods for adjuvant therapy decision making including (LVI, Tumor Stage, etc) that are imperfect at identifying patients with micrometastatic disease, and ctDNA offers a more sensitive and specific method that in multivariate analysis remains the only significant marker of prognosis after surgery (Reinert et al, JAMA Onc 2019).

In this rapidly evolving field I'm looking forward to additional data being generated with Signatera, and other tumor-informed assays like it. I'm excited for possible expansion of coverage for the assay to other disease types including breast cancer.

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

I am an Assistant Member in Interventional Radiology at Moffitt Cancer Center. I have been in practice for over 3 years and am involved frequently in the diagnosis and treatment of patients with recurrent metastatic colorectal cancer (mCRC).

I am pleased to support Medicare’s draft coverage decision for the use of Signatera in the surveillance of Stage II-III CRC patients after definitive treatment, as well as for adjuvant risk stratification after surgery. I view this coverage decision as a major step forward for patients diagnosed with early stage CRC. Based on the clinical data that has been published in several medical journals, the Signatera technology has been validated for accurate MRD and recurrence detection across multiple cancer types including colorectal cancer.

The clinical utility of Signatera is clear for patients in my practice, as it supports earlier detection of recurrence, perhaps prior to clinical symptoms or even imaging evidence. Early recurrence detection creates a range of therapeutic options for patients, hopefully leading to an improvement in their overall survival.

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

The Colorectal Cancer Alliance is the oldest and largest patient advocacy organization dedicated solely to the prevention of colorectal cancer and providing services to families facing this devastating disease. Some of the most heart-breaking calls our Patient Navigators receive are from patients who have undergone surgery, have gotten their life back, but now find the disease has returned. Having an effective way to identify patients that are at higher risk for reoccurrence would aid in more effective clinical decision-making.

It is our understanding that molecular analysis of circulating tumor DNA provides a method to assess a patient's response to therapy and the risk of relapse in patients with colorectal cancer. Several studies demonstrate that Signatera successfully identified high risk patients and was of significant value in guiding clinical decisions.

We would encourage Medicare to provide coverage for Signatera. As the incidence of colorectal cancer is age related, Signatera is of importance to the Medicare population. Too often many treatment decisions are based on affordability and Medicare coverage of Signatera would ensure it is appropriately utilized to address relapse of colorectal cancer.

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

As a medical oncologist who has been treating CRC for the past 15 years, I am struck by the lack of progress in identifying and treating patients in the adjuvant setting. Despite tens of thousands of patients treated on adjuvant studies, our major advance during this time has been reduction of treatment duration from 6 months to 3 months in certain stage III patients. There has not been a meaningful improvement in treatment, and very little of the biomarker work to date has resulted in improved prognostication beyond TNM staging alone. There is a substantial need for innovation and better tools for risk stratification and treatment guidance in this adjuvant setting.

Circulating tumor DNA provides a minimally-invasive approach to assess presence of residual disease not detectable by imaging studies. The strength of the data with this assay is unlike any prior molecular diagnostic in the adjuvant setting, and is immediately clinically relevant. On the basis of this, I am strongly supportive of the current Medicare draft LCD for ctDNA testing for adjuvant risk stratification and surveillance in colorectal cancer patients. This coverage will open up important new tools to better tailor therapy and follow up for our patients. The specific methodology has substantial strengths including the very low rate of false positives, which is critical in determining treatment escalation approaches, and high sensitivity through serial surveillance. The available data is strong and suggests impressive performance of this assay, as validated by similar studies using research-grade assays with sequencing technologies.

Clinical management of adjuvant therapy can be complex, with a number of clinical risk factors utilized in stage II with limited strength of data, and a degree of uncertainty on duration of therapy for stage III patients. This has to be balanced by the competing risks and patient-specific preferences for guiding intensity of therapy, especially in the Medicare population. Availability of an assay with the performance characteristics of this proposed assay would be beneficial in clinical management of patients, and represents optimal application of novel technology to directly benefit our patients.

Please don’t hesitate to contact me if I can provide any more perspectives on this LCD.

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

I am writing to support the proposed LCD for Signatera in patients with Stage II and III colorectal cancer (CRC). As a board-certified medical oncologist, adjuvant treatment decisions and surveillance for recurrence remain some of the most challenging decisions for my patients with early stage cancer. The clinical tools we currently use to identify which patients would benefit from adjuvant treatment are largely rudimentary, without regard to the patient’s underlying disease biology. This is particularly the case in early stage CRC, where currently most decisions are made based on purely clinical and pathological risk factors. It is therefore not surprising that the absolute risk reduction associated with adjuvant therapy is small in all-comers – an effect of inadequate patient selection. And for those patients undergoing surveillance, many will be diagnosed with recurrence too late despite CT scans and CEA markers, and thus be unable to receive curative oligometastatic surgery.

Circulating tumor DNA (ctDNA) has the potential to better identify patients with residual disease after surgery and identify recurrence earlier, while still at an oligometastatic, and potentially curable, stage. Based on the results published by Reinert et al (JAMA Oncology, 2019), Signatera appears to be well suited for improving upon CEA for early recurrence detection and for better delineating the presence of micrometastatic disease after surgery. Based on these results, as well as the broad literature showing the clinical utility of tumor-informed ctDNA in early stage CRC, I support the current LCD draft as currently proposed.

This novel technology represents a breakthrough in the way we care for patients in the era of Personalized Medicine and has significant implications in several other cancers as well.

I look forward to the final LCD as well as additional data generated with Signatera. I am hopeful that over time clinical utility will be demonstrated in other malignancies as well, and that the LCD will expand to cover these disease types as such an approach would be tremendously helpful in more effective patient management.

Please do not hesitate to contact me if needed to provide additional information.

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

I am writing on behalf of the Blood Profiling Atlas in Cancer (BloodPAC) Consortium in support of the MolDX program’s proposed LCD for Signatera in colorectal cancer patients.

BloodPAC
BloodPAC is a public-private consortium that develops standards and best practices, organizes and coordinates research studies through its members, and operates a data commons to support the liquid biopsy research community. Data from retrospective studies run by members, as well as studies BloodPAC organizes, are aggregated and contributed to the BloodPAC Data Commons (BPDC) to establish an open, publicly accessible data commons for the global liquid biopsy community.

Our mandate at BloodPAC is to accelerate the development of liquid biopsy assays to improve the outcomes of patients with cancer. We do this via an unprecedented collaborative consortium infrastructure of over 30 members comprised of industry, academia, and regulatory agencies.

We know that advanced diagnostic tests, and blood-based ones in particular, are critical to guiding physicians in making the most informed treatment decisions for patients suffering from cancer.

LCD Comments
We commend MolDX for this well-constructed draft Coverage Determination. It is clear that with strong evidence in retrospective cohorts, a sensible policy for clinical utilization of NGS tools to monitor efficacy during active therapy can be formulated.

We also applaud the practical adaptation of the ACCE framework, in terms of addressing clinical utility. Whether via risk prediction, or impact of the Signatera test results on patient management, the draft LCD offers great promise in expanding the role of MRD in solid tumor indications.

It appears that MolDX preferences regarding the formal use of registries (e.g., CED or CDD) have evolved. If registries are not considered as an option in this case, it would be most helpful for MolDX to share current thinking about the pathways for future approvals and/or new indications that might be appropriate.

Thank you for the chance to comment on this important new policy proposal.

Thank you for your comments regarding the policy. Regarding Coverage with Evidence Development (CED), this activity is not allowed for contractors by CMS and can only be attained through central, national policy.