A Position Paper on ctDNA Testing in Clinical Trials
JCO PO author Dr. Philip Philip at Henry Ford Cancer Institute and Wayne State University shares insights into his JCO PO article, “Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group.” Host Dr. Rafeh Naqash and Dr. Philip discuss how prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers. Transcript Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are excited to be joined by Dr. Philip Philip, Chair of Hematology and Oncology, as well as leader of GI and Neuroendocrine Oncology. He's also the Professor of Oncology and Pharmacology, as well as Co-Leader of the Pancreatic Cancer Program and Medical Director of the Cancer Clinical Trial and Translational Research Office at the Henry Ford Cancer Institute at Wayne State University. Dr. Philip is also the Senior Corresponding Author of the JCO Precision Oncology article entitled, "Incorporating Circulating Tumor DNA Testing into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group." At the time of this recording, our guest’s disclosures will be linked in the transcript. Dr. Philip, welcome to our podcast, and thank you so much for joining us today. Dr. Philip Philip: Thank you so much, Dr. Naqash, for providing me this opportunity to be discussing this with you. Dr. Rafeh Naqash: This is a very timely and interesting topic. We've done a couple of podcasts on ctDNA before, but none that is an opinion piece or a guidance piece based on what you guys have done. Could you tell us what led to this perspective piece or guidance manuscript being published? There is some background to this. Could you tell us, for the sake of our listeners, what was the initial thought process of why you all wanted to do this? Dr. Philip Philip: The major reason for this was the fact that investigators were considering using ctDNA as a primary endpoint in clinical trials. Obviously, you hear my focus will be on gastrointestinal cancers. So, the idea was, can we use ctDNA instead of using the traditional endpoints such as disease-free survival, progression-free survival, or overall survival? And the question was, do we have enough data to support that in patients with gastrointestinal cancers? Now, the article obviously goes over some review of the data available, but the core of the article was not to do a comprehensive review of ctDNA use and the evidence so far, although we used that in really putting our recommendations. So, we really had to evaluate available data. But the focus was, what are the gaps? What do we need to do? And are we ready to use ctDNA as a primary endpoint in clinical trials? Dr. Rafeh Naqash: Thank you for giving us that background. Obviously, a very broad, complicated topic with a bunch of emerging data that you've highlighted. But most importantly, for the sake of, again, trainees and listeners, could you help us understand the difference between tumor-informed and non-tumor-based ctDNA assessments? Dr. Philip Philip: Sure. So, the tumor-informed is simply meaning that you're taking the genomic makeup or the DNA fingerprint of the cancer in a given patient, and you create a profile, and then use that profile to see whether that DNA is present in the blood. So, it's very simple. It's like barcoding DNA and then going and looking for it in the blood, which means that you have to have the primary tumor. When I say primary tumor, you need to have the tumor to start off with. It doesn't really apply, maybe easily, if you just have a fine-needle aspirate and things like that. So, you really have to have a good amount of the tumor for you to be able to do that. So, that's a tumor-informed, and from the name, you can easily understand how it's done, compared to the other one, which is uninformed, whereby off-the-shelf probes are used to look for tumor DNA. And again, they're based on prior experience and prior identification of the key DNA changes that will be seen in tumors. So, that's the difference between the two in terms of the principle of the test. The uninformed will not require you to send the original tumor that you're trying to test. However, the informed, you do. The turnaround time is, again, a bit different because, as you would expect, it's shorter in the uninformed. And the reason for that, again, is the initial preparation of the profile that is going to be used in the future when you do serial testing. The sensitivity has been a bit of a discussion. Initially, people have thought that tumor-informed assays are more sensitive, more specific, more sensitive, et cetera. But in our review, we come to the conclusion saying that we don't think that's going to be a major difference. And there are obviously improvements happening in both types of assays. The sensitivities have been improving. So, at this point in time, we do feel that you have two types of assays, and we didn't feel strongly about recommending one over the other. Dr. Rafeh Naqash: Thank you for that description. You mentioned something about sensitivity, specificity. Obviously, many of us who have ordered both tumor-informed and tumor-uninformed, we understand the differences with respect to the timing. The tumor-informed one can take more time. The uninformed one, being a sort of a liquid biopsy, may not necessarily have as much of a turnaround time. Could you briefly speak to those limitations or advantages in the context of the two versions? Dr. Philip Philip: I just really want to also highlight that when we say turnaround time, so for the tumor-informed assays, the first assay that we do will be requiring a turnaround time. But once the pattern has been set and the profile has been documented, the subsequent testing doesn't require much in the way of waiting. However, when you're using this for the minimal residual disease, then you have a window of opportunity to work at. That's number one. So, it means that in patients who have resected cancer, you may end up having to wait longer than the tumor-uninformed assay, especially if you don't have easy access to your material for the baseline material to send. And also, what we'd like to do is not do the test immediately after the operation or soon after the operation. Give it some time. There's a window where you can work at, and starting minimally two weeks after the surgery. But in my experience, I'd like to wait at least four weeks just to make sure that we got an accurate reading. Sometimes when you do it very early after surgery, because of the effect of the surgery and the release of the normal DNA is also, it may dilute the tumor DNA, and then you may get a false negative. So, basically, it depends on the clinical situation. And your question is, is one better to be used than the other? I think ultimately, it ends up with the turnaround time not being as much of an issue. It might be in certain situations, depending on when you see the patients after the operation or any definitive treatment you've done and you want to look for minimal residual disease. But in general, I don't think that's going to be a real major issue. Dr. Rafeh Naqash: I remember discussing this with one of the tumor-informed platforms with regards to this barcode you mentioned. They generate a fingerprint of sorts for the tumor on the tissue, then they map it out in the blood and try to assess it longitudinally. And one of the questions and discussions we had was around the fact that most of the time, these barcoded genes are not the driver genes. If you have a KRAS mutant tumor, it's not going to be the KRAS gene that they map out. It's something that is specific. So, is there a possibility that when you are mapping out, let's say, a metastatic tumor where there is truncal and subclonal mutations at different sites, that you capture something that is not necessarily truncal, and that does not necessarily reflect some other metastatic site having a recurrence? So basically, over time, you don't see a specific mutational pattern or the signature on the tumor-informed, and then you see something on the scan which makes you think, "Well, it was not the right test," but actually it could be a different subclone or a clone mutation at a different site. Is there a concept that could help us understand that better? Dr. Philip Philip: I think you raise a very important point. Although, I have to say from my practical experience, that is not a common thing to see. In fact, for some reason, we don't see it that often in any frequency that should, at this point in time, make us concerned about the serial testing. But what you were mentioning is a real challenge which can happen. Now, the question is, how often does the clonal evolution or the divergence happen to the point that it's going to be like a false negative, is what you're saying. At this point in time, we don't really have good information on that, or any good information, practical information. And when we went through the literature and we were looking for the evidence, that wasn't something which was there clearly telling us. Although, this is something that has to be studied further prospectively. And I don't know of a study, but I might be missing it, I don't know of a study which is systematically looking at this. Although it's a very valid hypothesis and theoretical basis for it, but in real life, we still have to see how much does it really interfere with the validity of this kind of testing. Dr. Rafeh Naqash: Which brings us to the more important discussion around your manuscript. And I think that the overarching theme here is the consensus panel that you guys had recommended that ctDNA-based metrics be used as a co-primary endpoint. Could you tell us, for early-phase trials, maybe phase two studies for that matter, could you tell us what were some of the aspects that led to this consensus being formed from your working group? Dr. Philip Philip: Well, there were a number of reasons, in any order of priority, but one of them is we don't have a good sense of dynamics of the ctDNA. And again, remember this article was about gastrointestinal cancers. Maybe we know more about colon cancer, but, or colorectal cancer, but we don't know that well about the upper GI, like gastroesophageal, pancreatic, et cetera. So, we don't know what is the false negative percentages. And in fact, we know that there are certain sites of the disease, metastases, that do not lead to enough shedding of the DNA into the circulation. So, that was something else. I mean, false negativity, not knowing exactly what the dynamics are, especially in different disease types. So, that was another reason, which we felt that it may not be at this time primetime to really have those ctDNA tests as a primary endpoint. We wanted to make sure that, on the other hand, we wanted to make sure that people consider including ctDNA more like a secondary endpoint so that we can gain the information that we're lacking, at least the ones I mentioned to you. So, that was an important point of our discussions and deliberations when we were writing the article. Dr. Rafeh Naqash: And I myself have been on both sides of the aisle where - I treat people with lung cancer, you mentioned appropriately that most of the data that we have for ctDNA is generated from GI cancers, especially colorectal - on the lung cancer side, I myself had a patient with an early-stage cancer, had treatment, surgery, immunotherapy, and then had ctDNA that was tumor-informed, was positive four to five months before the imaging actually showed up. And on the other side, I've also had an individual where early-stage lung cancer, surgery, immunotherapy, and then had PET scans that showed a positive finding, but the ctDNA, tumor-informed ctDNA, was negative multiple times. So, I've seen both aspects of it, and your paper tries to address some of these questions on how to approach a negative, radiologically negative imaging but positive ctDNA potentially, and vice versa. Could you elaborate upon that a little bit? Dr. Philip Philip: Well, obviously, we do see this in practice. Again, I do GI oncology. I have patients who, you do ctDNA. I mean, my advice to anyone, when you order a test, you have to make sure that you know what you're going to do with the test, because that's the most important thing. You get a positive test, you do something. You get a negative test, you do something. But most importantly, our patients who you're following up, they are very anxious for a diagnosis they have that is not- I mean, it's cancer. If you're doing these tests, if we get continuous, repeatedly negative testing, then you really have to also tell the patient that there's a false negativity. And I mentioned to you earlier, there are certain sites of disease, like peritoneal, they may not be producing enough, or there are some tumors, their biology is such that they don't release as much to be detected in the blood. Now, one day we will get maybe a more sensitive test, but I'm talking about the tests we have now. On the other hand, if you get a positive testing, you have to make a distinction for ctDNA in the minimal residual disease situation. If you get a positive test, there is enough evidence that the patient has a worse prognosis. There's evidence for that. No one can dispute that. Again, I'm talking about colorectal cancer where there are a lot of data for that. So, in that situation, there are studies that are looking, if you get a positive test in someone who you're not intending to give any adjuvant treatment, there are studies looking into that, both in terms of intensifying, like chemotherapy, in certain patients. And also, there's work being done, if you have a negative test in someone who has stage III disease, for example, or definitely stage II disease, they may not need to give them chemo. Those things are happening. But in metastatic disease, it's a different situation. Or even in someone who has received surgery, adjuvant chemotherapy, in those patients where they, whether they're now under, in the surveillance mode, those patients, if you have a positive, it may be positive. I had a recent patient like those, eight months before we saw anything on the scans. So, the question is, if you have a positive test, is there any advantage in giving them treatment, systemic treatment? Of course, we're assuming that the PET scan is negative. So, is there really any advantage in giving someone treatment ahead of time, before you see the imaging changes? That kind of data, in my opinion, is not really available or strong. You can always think of it in different ways, explain it in different ways. It's minimal disease, maybe you get a better response. But I don't know if we really can justify at this time. Therefore, in my practice, my own practice, I do not treat just a positive ctDNA. Again, that's different than after surgery when you're thinking of whether to give adjuvant treatment, no adjuvant treatment. But someone who's finished treatments and then you're just serially monitoring the disease, those patients, I do not treat them with chemotherapy. And that was something which, based on the literature we reviewed, there was nothing out there to definitely- I mean, if you see something positive, you will do a scan earlier, you will talk to the patient, examine the patient, whatever. But if there's nothing there, starting a treatment, that's not justified at this point in time. Now, you need to do a study like that. Definitely, you need to do a study. But I can tell you that from my experience, having been involved with study design and all that, it's not an easy trial to do. It's going to be a trial- at a minimum, it will take many patients, it will take longer time to complete, and there are a number of variables there. If someone is willing to put a lot of money into it, it can be done. But I can tell you that that kind of intention to do a study like that has been very much a challenge at this time. Dr. Rafeh Naqash: Of course, as you mentioned, the follow-up time that you need for a study like that is going to be very long to get to meaningful outcomes. Dr. Philip Philip: You need to be very patient to do such a study. But the problem with a very long study is that things change, standard of care changes with time, and the assays will change. So, that's why we don't have that kind of data. I'm not sure if there are people in the community or in the academic centers who do treat based on only positive ctDNA. The other thing is that you really have to always consider the psychological impact of these tests on patients and caregivers. Sometimes it can be really very stressful, burdensome to people to sit there just waiting for the disease to show up on a scan. And therefore, in my opinion, I'm not saying definitely don't use it in that situation, I'm just saying that you have to personalize it also, to see the patient who you would like to do it and then other patients who may not do it, or you think that it's not good for them to do it. And the patient also has to understand the outcome of the test and how you're going to be interpreting it. Dr. Rafeh Naqash: That's a lot of great insights, Dr. Philip, and I know you've been involved in trial designs. I'm sure NCT and cooperative groups are actively thinking and incorporating ctDNA-based metrics as one of the endpoints in their trial. I know of a GU study that's, I think it's an Alliance study, trying to de-escalate treatment based on ctDNA. I have one of my colleagues who's also a GU investigator at OU, he's doing a ctDNA-based, tumor-informed-based de-escalation. So, obviously, more and more data, hopefully, that'll be generated in the next couple of years. Dr. Philip Philip: But remember, these studies are not using it as an endpoint. They're using it as a means of optimizing treatment, which is a bit different. So, as an endpoint, can you do a phase III trial of, let's say, a thousand patients, and your primary endpoint is not survival, but you're saying, "Can I reduce the ctDNA, clear it earlier, or whatever?" That's the sort of thing this article was about. We can't do that at this time. Dr. Rafeh Naqash: I totally understand. Thank you for explaining the difference, and hopefully more to come in this space in the next couple of years. I briefly wanted to touch upon your personal career and journey based on all that you've done and accomplished. Could you tell us about how you started, what your journey has been like, and how that connects with what you're doing right now, including mentoring other trainees and junior faculty? Dr. Philip Philip: Well, when I was in high school, I wanted to be an engineer, but I grew up in Baghdad, and all my friends wanted to do medicine, so I went with the tide, so I did medicine. I don't regret that. I would do it again if I had the opportunity. The reason why I did oncology was, I left the country and did a PhD in clinical pharmacology at the University of London. And that really got me, it was a topic which included, which was on cancer. So, I really got interested in a disease that is really a lot of science, and things are new, or were new at the time. And if I want to look back what I was doing, the beginning of my training in the 80s, second half of the 80s, and now, it's unbelievable how things have changed. But one of the things which I really have to say is that almost all my life I've been in what we call academic institutions. But I firmly believe that for people, whether academic or not, you have to be a very good, astute clinician, because many of the things we do, really, we're trying to put the patients in the center. It's not only doing fancy science, it's to do things that help the patients. And you can bring in bits and pieces of fancy science or less fancy science, but that's something which is really extremely important for us to think about, being a very good clinician, very good doctor, because medicine is a science, whether you're practicing as a solo practitioner or you're part of a large academic center. It's the way you think, the way you interrogate things that you're not sure of, the way you collaborate, the way you learn every day. I mean, at my age, I still don't like to miss any tumor board, because in each tumor board, there's something you learn, even if you think that you know everything. So, that's really the whole thing of it, is that be a very good clinician, be open-minded. Always, you have to think of things that, they look interesting, they look somehow unexplained. Always try to help find the solutions and do that. One of the major things that I feel that people should do is being also very focused on things. I mean, you have to also know what you want to do in the next 5, 10, 15 years. Because although everyone is in it in the same way when we start, but there are different things that drive people, people who want to do more of the formal research, like being an academic-like institution. But there are also a lot of people who are very successful outside of a- what we call an academic setting. In the United States, most people are not working in an academic kind of setting. Although, for me, the distinction between academic and community is getting less and less, because if you think that you do phase I trials in academia only, that's not true, because there are, in fact, in the state of Michigan, the most active phase I doctor is not even in academia, he's in private practice. So, you can do all these things. It's a matter of what you like to do, and you really have to make sure you know what you want to do. Because sometimes people are, especially early on, they get a bit confused, “What I want to do.” There's an issue of doing general oncology versus subspecialist. If you're a subspecialist doing only GI, you have to make sure that you really also have some kind of recognition that you're only a GI oncologist, recognition regional, national, international, but some degree of recognition that you feel that people are coming to you for advice as a second opinion or whatever it is. But again, you have to decide what you think you want to be, how you want to be, because there's a lot of options here between community practice, academic practice, industry, and of course, there's always the administrative thing. Some people tend to be more like going into the line of being an administrator. So, there's a lot of options for you. Dr. Rafeh Naqash: Well, thank you again, Dr. Philip, for those pearls of wisdom. I think that was very insightful. I'm sure all the trainees and early-career investigators will find all that advice very helpful. Thank you again for joining us today. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Philip Philip Disclosures Honoraria: Bayer, Ipsen, incyte, Taiho Pharmaceutical, Astellas Pharma, BioNTech SE, Novocure, TriSalus Life Sciences, SERVIER, Seagen Consulting or Advisory Role: Celgene, Ipsen, Merck, TriSalus Life Sciences, Daiichi Sankyo, SynCoreBio, Taiho Pharmaceutical Speakers' Bureau: Incyte Research Funding: Bayer (Inst), incyte (Inst), Merck (Inst), Taiho Pharmaceutical (Inst), novartis (Inst), Regeneron (Inst), Genentech (Inst), halozyme (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), merus (Inst), BioNTech SE (Inst) Uncompensated Relationships: Rafael Pharmaceuticals, Caris MPI
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