MolDX Open Public Meeting - October 28, 2020 - JF Part A

JOCELYN FERNANDEZ:
Let's begin our meeting.

Good afternoon and welcome members of the public to the Open Meeting for the proposed LCD MolDX Minimal Residual Disease Testing for Cancer. LCD number D L D like in David L 38814 for Jurisdiction E, and DL38816 for jurisdiction F.

The meeting will be recorded. The audio recording and written transcript will be posted on our website following today's meeting.

All lines are currently being muted by our system and will remain muted throughout the meeting. Only registered commenters will be allowed to comment during today's meeting. For the commenters, each of you are being allotted  10 minutes to make comments. Your line will be open when it is your turn to speak. Make sure you are not on mute within your system, or we will not be able to hear your comments.

You should be prepared to begin speaking immediately when called upon and will hear the moderator's voice when one-minute remaining.

By signing in today, you are giving consent to the use of your recorded voice as comments. Please be mindful of sharing any personal health information in your verbal comments. We ask that all comments made today also be submitted in writing.

While only registered commenter's will be speaking today, anyone in attendance may submit written comments. I will now turn the meeting over to Dr. Larry Clark.

DR. LARRY CLARK:
Thank you very much, I have been conversing with some of our commenters, just getting them lined up in order. Our last commenter scheduled for today, Dr. Eric Konnick, who is the assistant Director of the Solid Tumor Lab at University of Washington, unfortunately, had a conflict. So, he will not be here.

I think Dr. Bruce Quinn, also scheduled, will be moving into that slot, but this does give me a little bit of time following each 10 minute presentation to try and direct organized comments that have been made directly to a better understanding of some very complex material regarding DL 38814 and 16 is very interesting science here, and, I actually was up half the night looking at the slides, to make sure I knew what to ask. So anyway, our speakers, by the way, are a little too modest in terms of the slides we're showing you, compared to the accomplishments that they have accomplished.

The first two speakers are a product of the interest in this technology by two of the country's largest and most prominent cancer treating organizations.

The American Society of Hematology and the American Society of Clinical Oncology both expressed interest in participating in these policy deliberations. So, we will be progressing through a look at minimal residual disease testing. First in hematolymphoid malignancies and then in solid tumors.

Our first speaker today is Dr. Mary Elizabeth Percival. She is an Assistant Professor of Law, Medicine and Hematology University of Washington, Fred Hutchinson Cancer Center, and was the recommended expert on the subject matter by the American Society of Hematology.

Mary Beth, are you there?

DR. MARY BETH PERCIVAL:
I'm here.

DR. LARRY CLARK:
Hey, thank you so much for your effort. Thank you through the slides and the work you've put in, and unfortunately also having to rewrite this or formal written comments.

But I thank you, I thank ASH for recommending you, would you please go right ahead. Thank you.

DR. MARY BETH PERCIVAL:
Yes, I will. So, I am a Hemotologist, focusing on particularly patients with acute leukemia and even more particularly AML acute myeloid leukemia. And as you alluded to I'm a member of the ASH Committee on Practice and ASH will be submitting some formal comments on the proposed policy through that venue. So, next slide please.

So, I just wanted to focus on a couple of points which are listed in this outlined slide. When we talk about MRD, or, as it's written in the policy, minimal residual disease. But I should say that in malignancies, we actually usually call it Measurable Residual Disease keeping that M, and that's because minimal implies that MRD is as minimal importance are minimal significance and patients often hear that when you say that, it's minimal. But it actually is really important. And, so, now, we call it measurable. And, to that, I think vocabulary choice is really important. And, so, the three sort of points that I'm going to talk about in the slides that follow are that MRD is really important for prognostication and counseling. I'll focus a little bit on AML and ALL, but it's also really important. CML, Chronic, Myelogenous Leukemia, CLL, chronic Lymphocytic Leukemia, and multiple myeloma. There is an increasing amount of importance for therapeutic modalities that focused on MRD or switches in therapy, if MRD as detected, and then the last thing and this is, I think, speaking to the fact that perhaps this policy, while designed to be somewhat general is not general enough. Detection of MRD is more important than the method of detection of MRD.

And so, while we're focusing on molecular and NGS based methodologies, I'll talk a little bit about how there are some other things to consider as well. So, MRD in AML was first sort of recognized in the response criteria as in the 2017 European Leukemia Guidelines. The NCCN, the National Comprehensive Cancer Network, also included in a lot of these different subtypes. So, next slide.

So, this is just a summary of the Kaplan Meier curve with the error bars of a meta-analysis in ALL or Acute Lymphoblastic leukemia where I'd say that's one of the key malignancies Where MRD has been known to be the most important for the longest period of time. And so, you can see in the top two curves, this is really pointing to the prognostication and how important the presence of MRD is for counseling patients and really trying to figure out how best to discuss with them what their likelihood of their outcomes will be based on whether they have MRD or not. So, the top two curve event free survival, and the overall survival for patients with pediatric ALL, and you can see it just covers an immense number of patients. 11,000 in the top left panel, the panel, and 2800 patients in the top right panel, and there's just a huge difference in their survival and the event free survival depending on whether MRD is present or not. You can see in the bottom curve, three is less follow-up, because we're a little bit behind as adults, hematologic oncologists, and caring for patients with ALL, compared to how well the follow up has been done for pediatric ALL. But you can see similarly that there is a huge difference in the event free survival and overall survival for ALL. Next slide.

There was a recently published meta-analysis and AML or acute myeloid leukemia which is my specialty. This study was a meta-analysis of 81 studies and over 11,000 patients, and that really confirms the same sort of findings that we saw in that ALL meta-analysis, where patients who are MRD negative after their initial treatment had vastly improved outcomes. So that the difference in survival probability is really much greater. And you can see that when the overall survival and disease-free survival curves are almost overlapping like this. That means really that the reason that patients have problems when they have MRD, that can be detected is because the disease is likely to relapse. And I think this study and AML really underscores what's been known in ALL for a while. That the goal of any sort of treatment is to achieve an MRD negative CR. And if you don't know the MRD status, you probably need to figure it out because the outcome of your patient is likely to be very different. Next slide.

So, there are some cases where there are therapeutic changes that are performed due to detectable MRD so that they've been known for a long time and CML or chronic myelogenous leukemia.

Where, if patient still have detectable disease at a low level with that, that BCR ABL canonical translocation. Fusion protein found in patients with CML. That's certainly an indication to switch the tyrosine kinase inhibitor to a different one. So, that's been established for, you know, several decades at this point. In an ALL, a drug, blinatumomab, which is a bi-specific T-cell engager or BiTE. That was approved specifically by the FDA for patients who had MRD or measurable residual disease.

So, they don't meet the criteria for a traditional relapse, or they have persistent disease after initial treatment and next drug is approved for that particular clinical setting.

In AML we now know the importance of MRD as I told you in terms and prognostication. We're still trying to figure out how that fits into the treatment landscape for patients. So, I did a quick search for AML and MRD on clinical trials.gov and that turned up 212 trial when I did that yesterday. Those aren't all interventional trials where patients are being targeted for having MRD and having that be the goal to eradicate MRD but it is something that is does a huge amount of interest to a lot of investigators, and there's really a burgeoning role for clinical trials to try to deal with this very difficult clinical situation of having MRD and knowing that the patient is very likely to relapse. So, I, for example and the principal investigator of an investigator-initiated study at our center, which uses an antibody drug conjugate known as  gemtuzumab ozogamicin, specifically for patients with MRD. We have another trial that's going to open at our center for patients who are about to undergo an allogenic stem cell transplant for AML and are found to have MRD. So, it's certainly an area where there are a lot of clinical trials because it really is a place where we know that patients don't have outcomes that are as good. as patients who are able to clear their MRD. I should say that allogenic transplant is a way to potentially cure MRD for patients with AML. But, not all patients with MRD are going to be eligible for Allo-transplant. So, we definitely need other options for patients who aren't going to be candidates, for a variety of reasons. And additionally, the outcomes for patients who have MRD, who go under who undergo transplant, are not as good as those who don't have MRD.Next slide.

I should also say that there is a giant precision medicine effort being led by the NCI, the National Cancer Institute as part of the NIH. Along with the co-operative group that helped to run a lot of clinical trials in AML. This study is going to be known as MyeloMatch and it's an umbrella trial with a goal of finding the right treatment for the right patient. And so, it's going to take newly diagnosed patients. But then it's going to do a lot. There will be samples collected at a lot of time points including after their initial therapy. And for patients who have persistent MRD, they want to try to study what are being called MRD, eraser drugs or mechanism. So, ways to erase the MRD and hopefully improve the outcome. So, this is a really important study That says just a slide that I took from Jerry Radich that is an Investigator at the Hutch, who has done a lot of lab-based studies correlating some of the outcomes of patients with CML when it sees when they have MRD.

I think that there's really a role for trying to figure out who is affected by MRD and how we can try to come up with appropriate trials that are going to target patients with MRD so that we can have appropriate approved treatments for these patients.Next slide please.

JOCELYN FERNANDEZ:
Doctor Percival, you're coming up on 10 minutes.

DR. MARY BETH PERCIVAL:
The last thing I wanted to talk about was that there are a lot of different methods of detection of MRD and I do think that the policy should perhaps consider that. We have spent some time talking about molecular testing, that's what the policy focus is on, but it's really important to know that multi parameter flow cytometry and carrier type are ways to also detect MRD for heme malignancies in particular, I think it's important to note that the sensitivity is usually about 10 times better on the marrow compared to the peripheral blood, and so that's something that's not really taken into account in the policy. Next slide.

Then, I wanted to say that this study, the Netherlands really showed that at least for AML, it sort of doesn't matter how you detect the MRD. So this is a cumulative incidence of relapse curve looking at patient to MRD was detected either by an NGS platform or by a multi parameter flow cytometry platform and patients who are positive by both in the purple have a much higher incidence of relapse than patients who are negative by both.

But in them that patients who are positive by one, but negative by the other, really still have a very high incidence and relapse. And so, we often, in terms of being able to appropriately care for our patients, need to be able to test to add multiple time points. And the detection of MRD is more important than the method of detection of MRD as I said previously. Next slide which is my last slide.

I just wanted to make a couple of specific comments on the policy. One is, I think that the phrasing at the beginning, saying that the patient has not been previously tested with the same tax for the same genetic content, is a little bit problematic, because we need sometimes to be able to monitor apples to apples with the same test at one time point, and then, following up after another type of treatment to see if we have been able to clear the MRD. I think that we should discuss AML and CML because they really are examples also of how MRD can be really important in heme malignancies. And then the last thing I just wanted to point out is that there is so much variability within the sensitivity of testing. I mentioned the bone marrow peripheral blood, the different methodologies for being able to detect MRD, then noting that there is really a lot of genetic heterogeneity both within different types of cancers, particularly leukemia within an individual patient and then also between different patients leukemias. And so, you know, we've uncovered a lot of that with our understanding of MRD and better molecular and genetic characterization. But it's still very much a field that is in flux and so we need to have policies that allow us to be able to be mobile and nimble when caring for our patients.

That's the end of my comment. Thank you very much.

DR. LARRY CLARK:
Thank you. I have a couple of questions for you, if you'd be so kind to hang on for a couple of minutes. Doctor Steve Allen, from your board, actually started as in wanting to have your presentation here because he actually said, you know, the policy actually started out in the realm of colorectal malignancy, and he said, Larry, you know, why are you starting there.

There's really more experience in the hematology and the lymphoid malignancies and Dr. Lieu, who is, coming up in just a minute, actually affirm that that he feels like we're going to catch up.

I'm going to ask you in your written comments, if you would address the fact that concepts that you introduced here today, how can they be better incorporated into this policy? Because it sounds like you are clearly identifying this technology as a way to identify allogenic BMT recipients. I mean, there are real clear indications that you mention today. Am I right on asking you that?

DR. MARY BETH PERCIVAL:
I think so, you know, there are a lot of factors that play into who is going to be eligible for transplant.

So that it's a little bit of a can of worms, but, you know, I think perhaps because cancer marrow or easy to get samples from. Maybe that's why we are more ahead of solid tumors, like colorectal cancer, like you alluded to, because we can get these samples and look at them. And so, I agree that we are sort of ahead of them.

And, yes, I think I would be, I'd be happy, in the written comments that, that are submitted to address that, because I do think that, you know, we really have an obligation to try to deal with the findings that we come up with, from a clinical perspective, for our patients. To direct them to appropriate therapies, and I was just e-mailing with another physician this morning was going to see a patient of mine with the MRD that detected by an NGS task or a particular gene mutation called NPM one. And it's been persistent after several cycles of chemotherapy. And so that really indicates to me into the trans planters or is it that patient is unlikely to be cured by chemotherapy alone. and really need to consider whether ALLO transplant for this otherwise, you know, previously healthy 50-ish year old guy is going to be a good option.

DR. LARRY CLARK:
Super. Thank you so much. Really appreciate the comments and look forward to your written comments and they may be both your own comments and on behalf of your organization.

So, thank you, Jocelyn's sorry I interrupted you.

JOCELYN FERNANDEZ:
Not a problem.

Our second commenter is Dr. Christopher Lieu.

Dr. Lieu, your line is open.

DR. CHRISTOPHER LIEU:
Thank you.

DR. LARRY CLARK:
He's like Dr. Percival, way to modest, what he didn't tell us, and what we should be putting on his slide, is, he is the vice chair of the National Cancer Institute Taskforce on Colorectal Cancer. So, with that introduction and his admission that he needs to catch up, Chris Lieu. Thank you.

DR. CHRISTOPHER LIEU:
Thanks so much, Dr. Clark and thank you for the opportunity to provide comments on CTE DNA and minimal residual disease. Thanks also, to Doctor Percival, for giving such a great background on heme. Malignancies. This will be a little bit more directed towards colorectal cancer which is my area of expertise.

And I'm giving good comments and representation for the American Society for Clinical Oncology or ASCO as well. Next slide.

These are my disclosures, none of which pertain to the information that I'm about to go over.

Next slide.

So, Doctor Percival gave a great background on the importance of minimal or measurable residual disease just, you know, in regard to these assays, just in general, these are very general comments in regards to this idea of detecting tumor DNA in the bloodstream and so certainly, the advantages of this, are that it's a stable analyte. We can do targeted genomic characterization off of this DNA. They're established biomarkers and numerous solid tumors and the short half-life of circulating tumor DNA actually allows for real-time interrogation of what's going on inside of the body at that time and we're going to focus more on that in terms of minimal residual disease. There’s the potential for doing, certainly high depth sequencing of this DNA as well. Next slide.

CT DNA is certainly not without its disadvantages. Not all tumors appear to shed detectable ctDNA. There have been some questions as to whether metastasis in the peritoneum shed detectable levels of the ctDNA. Although the newer assays appear to be able to capture that.

The methodologies for analysis are certainly complex, and it can sometimes be expensive. You may get a low amount of circulating tumor DNA and a blood sample, and it can be highly fragmented and the results can sometimes be affected by the patient's age and this idea that a person can develop some mutations within their bloodstream that have absolutely nothing to do with tumor. And you have to be able to reliably, you know, take away that signal through your analyzes. Next slide.

All right. So, what are the potential applications of this circulating tumor DNA in the context of detecting disease that you can't see? And so, next slide.

And so, this is the green bar that you see on this graph. Here is what we fear at solid tumor oncologists. And that is, if you have a patient whose tumors removed, you worry that there's microscopic disease that you simply cannot detect with a CT or MRI or any type of radiographic imaging. And so, the green bar is the concern is that you when you give chemotherapy after a period of surgery, you still continue to see nothing on radiographic imaging and then when you stop chemotherapy, that's when we have, you know, very, very difficult visits with patients where we see tumors on a CT scan that were probably there all along. They were just microscopic in nature, they were allowed to grow, and then suddenly, you have a situation where you have Stage IV uncurable disease.

24:46

Certainly, the dotted line is what we want to see where you can use an assay that is better than our current imaging detection methods to reliably say that a patient has no tumor left in their body. And that is the power of ctDNA and minimal residual disease testing. Next slide.

So, you know, I kind of joked with Doctor Clark earlier. And Dr. Percival, you know, had a great presentation to kind of prove this point, that minimal residual disease or as Dr. Percival mentioned, measurable residual disease. It's a very well-established concept and hematologic malignancies that we're just now catching up to you and solid tumors, and so this idea of these MRD assays is that they're enabled by two, very, very key points. one is that there's a very high positive predictive value, so they're low false positives, I'm going to show you data on that.

And that this is not a marker of high risk in solid tumors we have a tendency to give chemotherapy after a cure to surgery based on this concept of risk, will a patient have a high risk of recurrence or will they have a low risk of recurrent? And these are just some tumor characteristics that we use sometimes to help us determine whether somebody's high risk or low risk.

If you detect circulating tumor DNA, it defines a molecular persistence of disease, which is really well established in hematologic malignancies, but this is the first time that we've really been able to identify this in solid tumors.

And so, when you have a patient that has positive ctDNA after cured of surgery, they're not cured of their disease and they should actually be considered to have Stage IV MRD. Next slide.

And so, I'm going to show you a couple of studies that show the power of this and Doctor Percival showed some data. In heme malignancies, I'm going to show some data in colorectal cancer. This is a study done in Australia where they removed the primary tumor and developed an ad say to look for the mutation that they found a tumor that's giving like a personalized assay, for each patient looking for circulating tumor DNA and the bloodstream. Next slide.

The numbers here are quite small, but you can see here that if you are ctDNA negative post operatively you had an incredibly low chance of having recurrence over the next 4 to 5 years.

But you can see that if you had positive ctDNA and again it's lower numbers but the three-year relapse free survival was the represent which means that which meant that every single patient had relapse. It had 100% positive predictive value. Next slide.

And so, this is the real power of this, and I'm going to show you several studies that have somewhat small numbers, but they all tell the same story and incredibly high positive predictive value and a very, very high negative predictive value as well. Next slide.

This is another study using a different type of assay looking at stage two and stage three, colorectal cancer and again the similar story where if your ctDNA negative the relapse free survival is outstanding. And if we see the ctDNA positive literally, within you know 3 to 5 years, you are absolutely 100% guaranteed to have a relapse if you have colorectal cancer. Next slide.

And this slide is really going to harken back to one of Dr. Percival’s comments on the current proposal as written. And what you're seeing here is longitudinal ctDNA and relapse free survival in patients with colorectal cancer and this shows you that, you know, the assay is powerful, yes, especially when you get it, you know, post operatively but serial testing leads to higher sensitivity and higher specificity. And just like the studies that I've shown you before, the ctDNA negative group had an incredibly great relapse free survival and 100% risk of recurrence.

And it just shows you that serial testing here does improve sensitivity and specificity. So, my comment will echo what Dr. Percival’s comment was, as well, next slide.

I know, as Dr. Clark mentioned, the National Cancer Institute Colon Cancer Task Force actually had a workshop on circulating tumor DNA and met several years ago at the ASCO Annual Meeting, really, to identify the promise of this technology, but, also, areas for investigation - utilization of, that, then, one of the primary conclusions that, this working group came, came up with, with the use of ctDNA for the management of minimal residual disease, as a key concept, for future clinical trials. But, also, clinical management, as, well.

Next slide.

Just some final thoughts. I gotta tell you, you know, ctDNA. It's certainly a powerful tool, represent a big leap, I believe, in terms of, truly, what has come to be the most prognostic tool that I've seen in colorectal cancer to date with extremely high positive and negative predictive values And certainly blows away any of our current surveillance studies that we currently use in the clinical setting will tell you, again, to serial testing appears to enhance sensitivity and specificity, which is critical for a patient. In complete openness and transparency, there are several things that we don't know that we will in the future. Will ctDNA MRD result you know, result altered clinical practice and, and, and the simple answer right now is that we, we really don't know.But with the sheer power of the product prognostic power of this tool, I know you might imagine that if somebody CTD and a positive, you would certainly increase surveillance. And the question also being with these results, improve overall survival and you know certainly registry studies and clinical trials will answer that question over the next couple of years. But you might imagine that if you can catch a patient with colorectal cancer, with recurrence early, you can increase the rate of potentially having a curative surgical resection in the future, which is certainly what we're going after. Then you know on a personal note, several of my patients have utilized these essays to make a determination in regard to their choice of whether or not to receive adjuvant chemotherapy, where patients that were ctDNA negative felt maybe a little bit better in regards to their choice. Not to do chemotherapy and patients who are positive ctDNA, certainly opted to escalate  their therapy because of the high risk, and what that next slide. I'm happy to take questions.

JOCELYN FERNANDEZ:
Thank you, Dr. Lieu for your comments. Dr Clark, do you have any questions?

Doctor Clark.

DR. CHRISTOPHER LIEU:
Doctor Clark, you might be muted.

DR. LARRY CLARK:
I sure am, Thank you. Yeah, I was going to say thank you again, and thanks to ASCO for recommending you and the University of Colorado.

On slide 24, you had a positive predictive value of 100% in the three year, excuse me, three  occurrence prediction. That's correct, I mean, that study was 100% positive predictive value.

DR. CHRISTOPHER LIEU:
Correct. And, you know, I think it's anytime you see triple digits. I think it's kind of hard to believe. And a caveat on all of that, of course, is that, you know, these aren't, you know, hundreds of thousands of patients, right? and so, know, that these are all smaller studies that I've shown you. I think the key take home point is that they're literally all showing the same thing. That the true positive predictive value, one would presume, isn't exactly, you know, isn't going to be 100% every single time. But any study that really comes anywhere close to that, and all three studies, actually, do show you what it looks like to be, 100 % positive predictive value. It shows you the powerful nature of this tool, and really does prove home the point that these patients are not low risk or high risk. They are; indeed, you know, Stage IV disease and so, you know, I think additional data will come out over time, one study. It's hard to really make any firm conclusions on, but a multitude of studies all showing the same thing certainly has significant weight and I think that that's why we're having a discussion that we're having.

DR. LARRY CLARK:
Right, thank you, well, yes, I mean, I just found that remarkable.

How about the flip side to that do you have any patients that are ctDNA positive but yet not progress towards the recurrence of the disease or patients who may be treated for recurrence of neoplastic disease that didn't need it and I know that would be hard to figure out, but, I mean, do you have any evidence there? There may be normal or successfully treated with circulating ct DNA that are not going to progress?

DR. CHRISTOPHER LIEU:
And so, I don't have any anecdotal examples of that. There are other studies that are out there with different assays that, that show that there are patients with ctDNA present that, you know, have yet to recur, although it is obviously, a vast minority of patients. On the flip side, we also know that there are patients that are ctDNA postoperatively, receive adjunct chemotherapy and are able to clear ctDNA, and it does appear that the prognosis for those patients is certainly improved compared to patients who are either unable to clear their ctDNA, or clear their ctDNA, but then have it return. So, there are several of those things that we know now, I think that, you know, some of the ongoing studies will further kinda refine that population to potentially utilize this assay to determine who may or may not receive chemotherapy in the futurr, but those studies have to be done.

DR. LARRY CLARK:
OK, All right. And the $64,000 question, or showing my age, probably a lot more money now. Yeah, but the question is, because you deal with, you're in the department of GI diseases at University of Colorado. Are you using this directly now in the treatment of colorectal cancer and how are you using?

DR. CHRISTOPHER LIEU:
Yeah, and so, the answer is yes. Right now, we are not offering this test to all patients.

I think that I, you know, for an academic institution, you'll find more and more patients being routed to clinical trials to help them answer some of the questions that have come up. But I, but anecdotally, I've had a decent amount of experience ordering this test for patients, particularly in a setting where they're pretty convinced that they really don't want chemotherapy, or they do want chemotherapy, in settings where it may not be recommended or may be recommended and these assays have actually been very helpful in guiding patients in terms of their decision making and I think that, you know, several years ago, I would say the data was not there to help you guide patient decision making. I think that the data that I've shown you now proves that. I think there's enough data out there to say that, you know, the accuracy at this test can really help patients and providers make critical decision making.

DR. LARRY CLARK:
Last question, sort of a theoretical one, for the future. There are assays and stuff out there that are now talking about. I would say a screening perspective. Utilizing ctDNA, are you endorsing? Or looking towards those concepts in any way or are they still theoretical?

DR. CHRISTOPHER LIEU:
So, it's a little bit of both. You know, right now do the essays, you know, or are those ready for clinical practice. And I would say it's still a little bit early. But as you get more and more assets that are out there. Looking at this for a universal cancer screening. I think over the next couple of years, you're going to see an abundance of data come out showing the power of this to potentially, screen for cancers, and so, the answer is, yes, we have a very, very big research interests, as many, many NCI designated cancer centers do.

In this, kind of, almost in the primary prevention side of cancer. But I think it's more in collaboration to acquire more data, before making any true clinical decisions based off of those assays.

DR. LARRY CLARK:
Thank you, both of you have been remarkable, I mean, I wasn't kidding that I stayed up reviewing the slides and our research analysts are already collecting all of your references from the slides. It's really remarkable discussion and thanks to both of you. Thanks to ASH and ASCO, and Jocelyn, turninf it back to you.

JOCELYN FERNANDEZ:
OK, our third commenter is Benjamin Eckert. Mr. Eckert, your line is open.

BENJAMIN ECKERT:
Thank you, Jocelyn.

Thanks to Dr. Percival and Dr.Lieu. My name is Ben Eckert and I head up market access for Adaptive Biotechnology.

So, coming up from physician Oncologists perspective, but from the perspective of Company a developer that's been in the MRD space for a long time and has as a really important MRD product in use around the country, and really around the world for patients with Lymphoid cancers.

So, first, Dr. Clark thank you very much for setting up this open meeting and having a really dedicated discussion on the role of MRD in cancer.

It's one that's near to or just quickly it about Adaptive. Adaptive is a Seattle based company.

That's been a pioneer in the field of immune sequencing since its founding out of the Fred Hutch Cancer Center in 2009.

And our clonoSEQ® assay is a next generation sequencing assay for the assessment of MRD in patients diagnosed with lymphoma malignancy specifically.

clonoSEQ® is the only FDA cleared MRD assay available for patients with lymphoid cancers in the U.S. as of now, it received FDA de novo authorization in 2018 for patients with ALL and multiple myeloma and just recently, for patients with CLL or chronic lymphocytic leukemia, earlier this year. clonoSEQ® is covered by Medicare, and has obtained really widespread commercial payer coverage adoption, over the course of the last couple of years, since its FDA clearance. The assay, as it now is used, as I noted, pretty broadly across the US. So it's utilized in all 30 NCCN centers, as an example, in many of the leading community oncology networks around the country. The evidence base, underlying classics, incorporation of care, has been supported by a pretty vast literature base now, 65 or more studies that have specifically looked at clonoSEQ® in lymphnoid cancers. But also, as Dr. Percieval noted, it rests upon on a wide variety of literature and meta analyzes supporting the role of MRD.

I note that adaptive continues to make significant additional commitments to evidence generation. So we're involved in more than 70 ongoing prospective studies across a range of lymphoid cancers to really explore further the role of MRD in, you know, wider variety of tumor types.

Lastly, and most importantly, NGS emerge the assessment, noted that the kind of clonoSEQ® is a NGS based tool is supported in NCCN guidelines and in several other international guidelines and has been for a number of years in a allow in ALL multiple myeloma and more recently in CLL and really did the role and an understanding of the importance of MRD is only getting more, more and more critical every day we look at the Olympic cancer space specifically, but particularly with the evolution of treatment in the cancer space. The important to them are getting patient care use is only increasing.

Again, Dr. Clark really appreciate the work that that you at Noridian and MolDX has done in the development of this foundational policy for MRD and just wanted to note that we are definitely supportive of the draft policy. Although, we believe that there are changes the draft policy, but that would help ensure a clear rationale and sustainable approach to coverage in this dynamic space and I just want to touch on a few of those topics today at a high level. And we'll be providing additional details in our written comments.

The first area is this is somewhat along with Dr. Percival made is that while we believe the LCD covering the role of MRD in both hematologic in solid tumors is certainly viable. The LCD could be improved to better recognize and respect the differences that exist between MRD assessments in these different contexts, and across different technologies.

One example, Dr. Lieu both Dr. Percival and Dr. Lieu eluded to this, and this is that the current Draft LLC focuses primarily on the use of circulating tumor DNA or cell free DNA as a basis for MRD assessment. However, MRD assessment in the Lymphoid cancer space is more commonly based on more direct assessment, the quantification of cancer cells themselves. And, that's commonly done in and either bone marrow or blood samples compared to other technology The LCD should also recognize that different NGS applications are used across different cancer types to assess and monitor MRD.

So, we think it will be important that the LCD develops specific performance criteria that are that are more closely tied to those specific tumor types and the technologies that are used.

Mutation panel-based technology is, is somewhat different than what we do in the lymphoid cancer space, clonoSEQ®, which is, which is based around assessment and immune sequences and quantification of those immune sequences and, so, we think, there are ways to improve that.

Um. We're supportive of, you know, the, the Draft NGS LCDs coverage for several of the Lymphoid cancers that are noted above ALL myeloma and CLL and thank Dr. Percival for her comments around additional hematologic malignancies where MRD is critically important ALL and CML as well.

We would also note that there's, there's a fairly robust, but also growing evidence base for MRD in patients with certain non-Hodgkin’s lymphomas and we would hope that Noridian and MolDX would consider perspectives from the clinical community around the role of MRD in treating these patients as you finalize the LCD as well.

The final topic or comment that we'd like to make is that the draft LCD establishes coverage of MRD as a series of assays and the patient with cancer and we definitely agree that this can be viable approach is needed. However, we'd like Noridian and MolDX to explore whether this episode of testing framework may no longer be required for MRD assessment given changes to the language of the 90.2 NCD following the reconsideration. We believe that MRD could be covered on a pretense basis in accordance with how Medicare covers MRD performed by other technologies, such as flow cytometry or PCR and that would provide significant significantly more simplicity to the coverage of MRD and we'll be making comments in more detail on that topic in our, in our written comments.

So again Dr. Clark, I'd like to thank you for pulling this meeting together and really look forward to working with Noridian and MolDX toward the finalization of this policy in supportive Medicare patients with lymphoid cancers.

JOCELYN FERNANDEZ:
Thank you, Mr. Eckert, for your comments, Dr. Clark, any questions?

DR. LARRY CLARK:
Yes, I do, then, I guess, you know that they're being a stakeholder representative doesn’t spare you getting questions. First one, I like your comments on the reconstruction of the policy were very direct would you say we would be better served If we split it out solid tumor, the use of MRD in solid tumors, from hematological malignancies, lymphoid malignancies? Should we have separate policies, How would you organize our approach? Do you want to talk about that now, and certainly, talk about that in the written comments.

BENJAMIN ECKERT:
Yeah. I'll just make high level comments now and provide more detailed comments.

But, now, as I said, I think, I think it's a, it's certainly a viable approach and, sort of in recognition of that the main theme that that, you know, MRD as a concept is relevant to a number of cancer types now. So, we do think it's a viable approach to include it within you know, a single foundational LCD.

But, but, yeah, we do think that it may be helpful to think through in a little bit more detail maybe sort of within the construction of the of the LCD breakout with a little bit more detail and more thought to put two potentially different criteria for coverage amongst the different sort of malignancy types.

DR. LARRY CLARK:
OK, OK.

The other thing that I would hope that in your comments, you First of all, we're covering you as Medicare, either under the NCD 90.2, is that we're covering you as NGS Correctly, that we're covering you now.

BENJAMIN ECKERT:
Correct.

DR. LARRY CLARK:
And did you have any thoughts or comments? Or maybe, your representative, Dr. Rudolph would like to address that in your comments.

She mentioned the other modalities such as FISH and a specific type of flow cytometry as providing alternative results.

Do you have any experience or comment on those other modalities at anything it Adaptive is into? Or no?

BENJAMIN ECKERT:
Adaptive is not, you know, in in the lymphoid cancer space, let's say Flow Cytometry is it another modality for MRD assessment and I believe there are other, know, Medicare policies broadly that that address MRD is as one of the one of the applications of a flow cytometry so I don't know that it would necessarily be relevant to bring in non, sort of non-molecular technologies into this into this LCD.

DR. LARRY CLARK:
I wouldn't, I don't think. That's my inclination. But, I mean, you have actually made some specific comments about the way we organize our approach and I would really appreciate, if you continued. Then, just one question, is Adaptive Biotechnology looking into any applications of this as a screening test, I mean, it does present us as Medicare, with a little bit of difficulty because of the traditional statutory definition of the program, and so, there is sort of an overlap. In some places. Are you folks doing any research in that?

If you can't tell me OK, yes, if you didn't talk about it, you're right. Sorry about that.

BENJAMIN ECKERT:
Yeah, no, not for clonoSEQ® we're not. So for clonoSEQ® it’s FDA authorization is for patients with diagnosed malignancy in that, in those types and talked about.

DR. LARRY CLARK:
Hey, thank you. I really appreciate this. I think this is really policy focused and I really like it. Jocelyn.

JOCELYN FERNANDEZ:
All right. Our fourth commenter is Dr. Paul Rudolph. Dr. Rudolph, your line is open.

DR. PAUL RUDOLPH:
Yes, this is Paul. Can you? Can you hear me now?

You're loud and clear.

I wasn't sure I've never used this platform before, and I wasn't sure I was hitting the right buttons. So, thanks for the privilege of being able to say a few words here Dr. Clark and Noridian I'm Paul Rudolph. I'm a partner at Arnold and Porter, which is a law firm in Washington. I represent a lot of clinical labs, including Adaptive. As Dr. Clark knows, I used to be a Medicare contractor medical director and I used to work with Medicare Central Office for a number of years, developing policy on a number of things, including lab testing.

My short remarks today are really coming from the perspective of a former medical director and hopefully, might be helpful to Noridian and Palmetto. In listening to the presentations. Today, it seemed relatively clear to me that the state of the evidence for hematologic and lymphoid malignancies is rather different than the state of the evidence for solid tumors. And I think there's someone that used to make policies on these sorts of things.

It would be a very good thing for the community to have, to different parts to the policy. That clearly one part is for solid tumors and the other part is for heme and lymphoid tumors because it appears that there's going to be used somewhat differently. The accuracy, the predictability, or predictive value are different, and it seems to me that the community needs will have different expectations for tests that are covered for heme and lymphoid malignancies as opposed to those that are covered for solid tumors.

I would also point out that that's a very difficult thing, but one that I think is important, is that the policy be looking forward enough so that it doesn't have to be revisited and reconsidered every few months. Every time a new test is on the market. Meaning that there should be clear criteria, performance criteria for the tests that are recovered, so that those stakeholders that are developing new tests, including Adaptive, will have new tests, for example, that they very clearly know whether they are covered or not, and they can, they don't have to ask for reconsideration. Rather, they can be covered and Noridian and Palmetto can have a mechanism for just making sure they're covered and making sure that the claims are being paid.

The second set of remarks I want to make, and I will also say something about the episode in a minute. I've been reading the draft policy very carefully and the draft policy has seven different provisions for the limited coverage. I wanted to say that as a former medical director and as someone who advises labs, I sound a few of the proposed provisions a little confusing. And I think that in the final version, they really should be clarified, and specifically, I'm referring to numbers 3 through 7. I'm sure that everyone on the phone has read this.

I don't want to read them back to everybody, but it was unclear to me what the draft policy meant about being included in NCCN or other established guidelines met. Does it mean that the test has to be included? Or does it mean that the disease has to be included as in such a way that that when MRD is positive that there has to be a change in the patient management or is it that the test has to have been identified NCCN itself? That was unclear to me.

The fourth and fifth – it was not clear to me what was meant about being more sensitive or as sensitive to other modalities, and a radiologic evidence of recurrence or progressions, and how that would be adjudicated or what Noridian and Palmetto are looking for so that the problems 4 and 5 have been met.

Then six, also, it seems that they're looking for explicit therapy and it seems to me that a lot of MRD testing in heme and lymphoid malignancies are not so much to determine whether one drug should be used or another, but just what he should be continued or not. So, I was wondering if six could be clarified and then seven also unclear what it meant by the test performance for new tests, be comparable to existing tests. I think that goes to some performance criteria that that really should be elucidated. Then the last remark I want to make is about episodes and in this, I want to go, back to the, one of the last remarks. That Dr. Percival made in her presentation.

I have been looking a lot at the language in the in the NGS NCD and it seems to me that the revised language that discusses the same test for the same genetic content does allow for a per test payment and coverage as opposed to per episode. Dr. Clark, I'll be working with Adaptive on their comments. I'm happy to talk with you or send something in more detail, but I believe as a lawyer very strongly that that that language does allow per test payment for MRD tests and I hope that Noridian and Palmetto will consider that. I understand that there may need to be some discussion with CMS Central Office about that. But I think that would dramatically simplify any final policy if tests could be paid on a per test basis because that would allow for tracking. It would allow for healthcare research, there's a whole slew of things I think that would be it would be very advantageous to cover in that way and with that, I will I will end my remarks, and if you have any questions, happy to answer them.

JOCELYN FERNANDEZ:
Thank you, Dr. Rudolph.

Doctor Clark, do you have any questions?

DR. LARRY CLARK:
I do think, I mean, and I will encourage you to, to help adaptive or in your own comments, or on behalf of other clients, delineate the performance metrics. I think that you really did go back to your CMD days in terms of that. In other words, if we're going to be talking about comparable to the levels, then we really need to define this into write this policy. Because I think what you're saying is going to be additional testing coming in, and that we need to establish some standards. Is that what you're saying?

DR. PAUL RUDOLPH:
Yes. I think so, and I work, I think Adaptive has some thoughts about that, but, yes, because, you know, Dr. Clark, I represent a lot of clients and if LCDs aren't written in the looking forward way. Every single lab has to request reconsideration for every single LCD just to get the name of their tests included, and as you know, the new process takes about a year. And that means that if you really have to reconsider an LCD every time there's a new test out there that patients are not going to have access to that test. Frankly, an existing test for new indication, Patient’s will not have access to the test for a full year and that's very frustrating for everybody and I think that's going be a challenge, for Noridian and Palmetto to create a policy where labs and let's just say hypothetically adaptive. They have a new test or an existing test with a new invitation that they've worked with Noridian and Palmetto to get it in there without having to ask the LCD to be reconsidered, which takes a year.

DR. LARRY CLARK:
Thank you and please include that in the comments. Dr. Rudolph is also to modest, before his legal career, he practiced and taught medicine for a whole bunch of years. In fact, when he moved over to CMS. I took his position at Trailblazer. So, without him, I wouldn't be here today. So, thank you, Dr.Rudolph. Jocelyn.

JOCELYN FERNANDEZ:
Our next commenter is Dr. Bruce Quinn.

Dr. Quinn, your line is open.

DR. BRUCE QUINN:
Hello, thank you very much, and thank you, Dr. Clark, for the way you're running this meeting with the informed questions and that it's really been great to listen to so far.

My name is Bruce Quinn and by training, I'm a pathologist, although I left, practice, in 2000, 20 years ago and I've worked in consulting and worked also as a medical director during that time, and, like Dr. Rudolph, I have clients in the lab space.

So, I have a few comments, also from the perspective of the, you know, the policymaker or the operations of the policy. It is important that LCDs be clear. When we're reading trade journals, we frequently hear that some lab has had 5 or 10 or 15 million dollars recouped from a RAC or OIG because it didn't fit a policy and of course, there could be bad actors that lead to that.

But there can also be policies that are ambiguous and that they really didn't understand what would later be expected of them. So, it is important for those millions of dollars reasons that the policies be clear.

There were a couple of things touched on here. One was that the policy you know has a discussion of solid tumors before hematopoietic tumors I think that they can fit together with some specifications. So, I think I would prefer leaving them together and leaving the details to articles and follow up.

I think the fact that the solid tumors come first is just a coincidence of the way it was happened to be drafted.

There was also some discussion about you know, therapies downstream like the MRD tests and hematopoietic disease can be a pivotal piece of information for doing allogenic stem cell transplants, Bone marrow transplants and while it's important that the test have clinical utility because it leads to something downstream, like a change in the inhibitor or a change in the bone marrow transplant plan. I think those things are largely outside of the policy itself, that once you know those things are occurring, you really want to focus on, on the entry point for the test, and not what happens afterwards, as long as those things later ensure clinical utility.

Another reason for writing a clear policy that medical directors regularly, every few years.

Uh, so, uh, the new medical director or the new auditor will have the written works of the policy and may not know what was previously intended, or how someone thought they were going to interpret it. So, that's another reason for it to be clear.

Um, so I have a couple of things not mentioned yet. One is that Noridian, and the other MolDX MACs are moving toward having master policies or foundational policies and underneath that, allowing specific tests and perhaps specific indications by the way of an article, Um, there is some concern that this takes away from Congress's intent and CMS intent to have public debate and public comment.

Um, so one company might have its test covered and another not, but they can't really see each other's technology assessments. There's no chance for public comment.

So, I think it would be good practice to regularly put up an abbreviated technology assessment, article some kind, so that different parties understand what's going on in the quote, closed rooms, where those technology assessments are done.

So, I think we need to keep some public visibility. The other thing is updating the technology assessments, or articles, billing articles regularly. There have been some foundational LCDs in place for a couple of years now, and whether tests are covered, or not, whether, you're lab or competitor is covered, or not, is sort of secret information, because they haven't gotten around to updating the article. So that's another reason for keeping the public visibility timely.

Um, as Dr. Rudolph was saying, you know, there are these seven bullet points, some of which are fairly confusing or vague. You know, the bullet points five is, you have to have comparable sensitivity to imaging and bullet point six, or 4 and 5. 1 is comparable sensitivity, and one, you have to be considerably more accurate than other established forms of surveillance.

So, as the Medical Director has changed from year to year or one medical director, and another medical director reviews another company, they may have very different ideas what quote considerably more accurate unquote means.

So, that's the kind of thing that, that I think we should make clearer, if we can and I like Dr. Rudolph's comments a moment ago about episode of care versus individual coding for each test given. I think the natural thing to do when you can do it is probably individual coding.

If you look at some area, like PET scans, or some tremendous work that was done earlier this year on databases and CMS databases in sepsis, we can really rely on those CPT codes as linchpins to doing public health studies and if you don't know if a patient got to 4, 6 tetss and you don't know if they occurred in one year over two years, then you lose that public health data aspect. which I agree with and which Dr. Rudolph alluded to. I think there have been some specific reasons that we have identified episodes of testing. But if we have to do that, we should, you know, have clear guidelines. So that different companies feel they're all treated fairly.

Those are my comments. Again, I think this has been an incredibly well-done public meeting, and I thank you for the chance to participate on it.

JOCELYN FERNANDEZ:
Thank you, Dr. Quinn for your comments.

Dr. Clark, do you have any questions?

DR. LARRY CLARK:
I sure do. I mean, but it's Like the CMD all-stars here.

Anyway, you talk about, know, you've raised a concern over a valid one. I'd like to hear your concern, particularly from the point of view of your blog, your, your writing, and your representation following along the lines, of all started, our blunting of congressional intent.

You know, we had been looking at the concept, and we heard Paul, when he said, You don't want to be writing. You don't want to be reconsidering every time another technology comes along and I appreciate the fact that you are promoting a concept of fairness to stakeholders so that we are approaching companies on an even playing field.

How do we ameliorate the different poles of what we're talking about? You're saying and one way it's blunted Congress's intent, but on the other hand, we have to slot in different technologies without going back policies over and over. What, what would you do?

DR. BRUCE QUINN:
Yeah, absolutely and I think these things actually are compatible with each other. When I referred to congressional intent. I was thinking of no requirements 10 years ago that NCDs have to go to a specific public comment statute and regulations LCDs, since the 21st Century Cures Act. Congress really laid down regulations for how LCDs have to go through public comment.

When LCDs still go through public comment, there is a special Appeals channel to an ALJ, depending on the ALJ regarding LCD record. So, yeah, Congress has asked, and CMS has asked, that these things have transparency and public comment. However, I think the individual TAs of different companies would go a long way just by summary, summarizing those and the fact that they would be summarized afterward and posted as an article, that would be a very strong deterrents to providing misleading information. So, just knowing that it's going to be publicly available later, is, is really sort of the stick, you know, that keep people honest and if it's all done a call and you can't get it through FOIA because it's a business secret, and you really don't know what that other company told Medicare privately. Maybe they exaggerated, but there's no record that you can get, I think that's bad. So, I think posting a tech assessment as in the form of an article would go a long way, and that way, if there's something egregious at that point, people can complain. It doesn't necessarily have to be public comment, but they could still, you know, raise issues after the fact.

DR. LARRY CLARK:
So, you're really looking at going back to the beginning of the process and including the technical assessment in terms of, let's say, the policy's history. Is that really what you're getting at?

DR. BRUCE QUINN:
I wasn't thinking, no, I was thinking not at the beginning, but on the rolling basis. So as new things are covered, and they have to meet certain criteria, as they're on a rolling basis, off into the future, I would publish status articles, what the tech assessment.

DR. LARRY CLARK:
OK, that's very interesting, and if you could write a little more on that, and would be willing to take the time, we would really appreciate it. Again, the last two speakers have put a policy development perspective, that, actually, I didn't even anticipate when we posted this meeting, so.

Thank you. Jocelyn.

JOCELYN FERNANDEZ:
OK, um, our last commenter, as Dr. Clark had mentioned, had to cancel due to a conflict.

So, we can move on to closing and next steps.

DR. LARRY CLARK:
Jocelyn, if you would go through the next steps, the timeline on the policy, and then I just have a couple of closing comments and announcements of upcoming meetings.

So, if you do that, and then I'll say, Thank you.

JOCELYN FERNANDEZ:
OK. In closing, we would like to communicate the next steps in the policy development process.

The comment period for the proposed LCD will remain open until November 22nd, 2020.

As noted earlier, all comments to be considered by our medical directors for the proposed LCD must be submitted in writing, written comments can be emailed to policydraft@noridian.com or mailed to the address on your screen. Information for our proposed LCDs are located on our website at noridianmedicar.com Upon review of the comments or medical directors will either finalized or retire the proposed LCD. Please monitor our for registered for Listserv notifications to be informed when actions are taken to implement or retire our LCDs. All right, Dr. Clark, you are on.

DR. LARRY CLARK:
All right, thank you.

On November 5th, at 3-5 PM Central Time will be 4-6, Eastern, and do the adjustments.

If you have to, but from 3-5 central on November 5th, either Dr. Sun or Dr. Moynihan, is going to be participating in an open meeting on colon capsule endoscopy. We will also be beginning the, the CMS notification process for the posting of our draft policy on wound care. So, the goal is to have a little bit of a delay in that policy because some of the coding and some of the provisions conflicted with an existing policy that involves ulcers in hyperkeratosis you know, predominantly involving the lower extremity. So, because of the coding conflicts, we retired a policy that was very particularly to podiatric medicine. So, we incorporated elements of an existing policy into care. I think this is going to be an extensive discussion. We may break it out over two days so that we give adequate discussion to everybody that wants to, to speak.

So, we're anticipating posting the policy, fourth quarter, 2020 and having, you know, the meeting discussion and finalization either late 2020 or first quarter 2021. So, with apologies for that delay, that is finally back on track.

With that, I really want to thank our, what a robust discussion, what multi-talented people we had speaking today.

Also, real shout out to our MolDX team in organizing this, and presenting the slides and all the information, and please comment, and let us know what you think about this policy.

Thank you very much. Have a good afternoon and evening. Bye-bye.