Clinical Value of ctDNA MRD Testing Beyond Standard Imaging in NSCLC: Precision Oncology Breakthrough vs Early Clinical Evidence (Round 2)​

To hear the arguments related to testing in immunotherapy selection for NSCLC, see Round 3.

Dr. Garon: Yeah, so this is obviously the extremely important topic, which is, I think that we've probably proved to you that at least in some cases this can be done. The question is really the clinical value. So, ctDNA MRD testing provides clinical value beyond standard imaging. So, this is a study that is out of Max Diehn's group at Stanford. And what they did is they looked at patients who had evidence of—who were known to have recurred after a curative intent treatment. And they analyzed all of these people for both circulating tumor DNA and CT imaging. So, we know that, you know, that these people have recurred. And the question is, which one shows disease first? So, I orient you because this isn't the way we're used to looking at a curve like this. We're used to looking at outcome. But what this curve is looking at is what is the time where you said, “Ah, we got it. We've shown that there's disease that is coming back.” And you can see in red, in general, in these patients who were known to have had disease recur, the ctDNA came back positive considerably earlier than imaging came back. Now, one of the big questions with this is sort of a philosophical one that we've often asked people, which is, “If you know that something bad has happened or is going to happen, do you want to know sooner or do you want to know later?” Obviously, if there's no potential impact on what you do, one can make a strong argument that there's no great reason to know sooner that something bad is going to happen as opposed to later. And that could be an hour-long discussion, in and of itself. It gets more into sort of philosophy and psychology rather than medicine. But, on the right, they show a case where this is helpful and a place where I think that circulating tumor DNA would have a very meaningful role. So, this is a patient who had stage III disease, had been curatively treated, and then had what oftentimes we discuss at our tumor boards and in our clinical practice. The scans didn't look quite right, but not enough to convince us that disease had come back and not enough to make us confident that it hadn't. But in this case, this was a patient who had high levels of ctDNA at baseline that rapidly reduced and stayed low. And this is, I think, a great example where if you knew that the circulating tumor DNA had been positive, it would be a very—you know, you would search further to see whether or not there's evidence of disease recurrence. But the fact that the ctDNA was negative was further supportive of the idea that perhaps this is just sort of post-radiation change and sort of inflammation that you would see. And, in fact, with two years’ follow-up, this patient had not recurred. This is an older study. This was also Max Diehn's group, working with many investigators, published by Matt Hellmann, who at the time was at Memorial. And what they did was they took a group of patients who were doing particularly well on immunotherapy. So, these people were like these good responders with immunotherapy. And they looked to see whether or not there was evidence of circulating tumor DNA in those patients. What you can see here is the numbers are pretty small. But I think I remember the numbers. I think it's like 27 patients who did not have evidence of circulating tumor DNA. Two of those patients did have recurrent disease. But you can see in the bottom—for you guys, the bottom left corner—you can see that most of the people in sort of the beige here do not have evidence of recurrence over time. The number of people who did have evidence of circulating tumor DNA was small. There were four of them. But those patients all recurred. And so, this, again, is suggestive of the idea that this is clinically helpful. Even this is a group who is on treatment. And one could evaluate is this person done with treatment, you know, with a fairly high degree of certainty, or does this person have evidence of residual disease? One place that I think is a particularly clinically relevant data set is the ADAURA study. Most of you are familiar with this study. Patients were randomized after resection for lung cancer. Appropriate patients got chemotherapy as well. And patients were randomized to receive either the third-generation EGFR inhibitor osimertinib or to receive placebo. And we can—you know, the data showed that recurrence was much greater in the patients who did not receive the osimertinib. But here, you can see up on the top, you can see that there was a group who had, you know, who did have evidence of positive circulating tumor DNA afterwards. And, you know, that was a group that tended to recur. That tended to be more in the patients who did not get osimertinib. And you can see, I'll sort of direct you to the pie graph. You can see, in gray, most of the people who got osimertinib did not have recurrence during the period that they were on osimertinib. Closer to me, you can see, in red—I'm sorry, in green—most of the people did recur if they had—if they were on placebo. But of the osimertinib, when they stopped the osimertinib, you know, there was a group of people who had disease recurrence—sorry, that had circulating tumor DNA positivity develop. And, in those patients, recurrence was generally seen. And in “B” here in the bottom left, I think is an interesting way of looking at this and in some ways maybe biologically how we think about this. So, what you're seeing here is a traditional Kaplan-Meier curve. But rather than sort of progression-free survival or the typical thing, they're looking for sort of recurrence-free survival or—MRD positivity was considered a bad outcome. So, it was part of a composite endpoint that either the disease recurred or they had MRD positivity. And you can see that there was a huge difference based on whether or not these patients received osimertinib for that endpoint. So, why is that an appropriate endpoint? Because I think with the data that I've shown you so far, I've probably convinced you that if you have circulating tumor DNA that is positive in the tumor-informed test after a surgery, your outcome is extraordinarily poor. And your likelihood of recurrence is nearly 100% in the data that we have had to date. And so, that's why they looked at that as an endpoint. So now, I'll pass this over.  

Dr. Raez: Okay, so for the ones that are not very familiar, this is the way that we measure tumors, the RECIST. We measure the long axis in the tumors. And in the malignant nodes, the short axis. And then, you know, if it's more than 30%, in tumors that had response, more than a 20% increase, we are failing terribly. So, this is our standard of care. We follow patients every three months. We CAT scan. And the other variant that I didn’t mention before and can take advantage to mention now is that we have two ways to do the MRD. The tumor informed, that basically we go to the tissue that we have from the patient and we prepare from the tissue the MRD, and we look in the blood. Or tumor naïve, that we get the blood, and we look for the ctDNA. So, this is two technologies, two controversies. Which one is better? So, when we're talking today about MRD, we're talking about both of them, you know? We still don't know which one is better. These are the challenges of MRD, that the sensitivity maybe is not enough. That's why I show you some results before. The cancers also are heterogeneous. It's not the same to do MRD for a brain tumor that there is no shedding in the blood, than a metastatic lung cancer or metastatic prostate cancer that you only have disease in the bones. So, that's why, as I said, a lot of these challenges of MRD are not in the test, are in other factors—or you see, for example, sampling errors, you know? It depends where you do the biopsy. Same as standardization, you know, we don't have a threshold. I like these people from—the best example is our colleagues that do bone marrow transplant. They have the standard of care MRDs since the year 2000. They are 25 years ahead of us. But I think the standard of care—I don't remember—it's like one cancer cell in a million. So, your MRD has to catch one cancer cell among a million cells. We don't have the standard yet. We haven't decided yet, you know? The same with interpretation, correlation with relapse, and decisions. And the cost, you know, we do CAT scans every three months in our cancer patients. There was a time that our lung cancer patients only lived a couple of years. So, it was not a big deal to do 10 or 15 CAT scans. Now, they live 10 years. I just lost a patient that was a good friend. They lived for 14 years. So, we did—I don't know—60 CAT scans on him. And nobody knows what is the tolerance or the limit before the radiation exposure starts to create problems. But the cost is the same thing. They said, “Oh, these MRDs are expensive.” But we do four or five CAT scans a year. So, if we can easily replace the four or five CAT scans a year for MRD, we don't expose the patient to radiation. And I guess the cost of MRD is being paid by the price of the four or five CAT scans. And the other problem is patient anxiety. Now that we are doing research in our patients—and some of these studies are blind. Some studies are not blind. The worst that can happen is when we have a negative scan and MRD is positive. And then, the patient said, “Now what do I do?” That's why we always—before we enroll the patients in the studies—we always warn, “Hey, there is a chance that one day the MRD is positive.” Fortunately, it's very uncommon, I think, very uncommon. MRDs are good, so we don't have a lot of false positives. But that can create a lot of anxiety with the patient as Dr. Garon was saying. “Now I am positive. I know that I'm going to do bad. But they don't do anything for me now because they cannot find the tumor in the CAT scan.” And, of course, there's ways to solve these problems and to increase the level of detection. I was mentioning here that the level of detections, we are in around 100—we are finding one cancer cell among 100,000. But there are technologies now that we have that we can detect one cancer cell among a million. So, maybe that's a solution. Another solution maybe is to—the way that we—another way that we find these MRDs is we analyze a piece. We get a single nucleotide variance inside a molecule. Maybe the solution is, to increase the sensitivities, is look for more than one. If we do this PhasEd enrichment, instead of looking for only one single nucleotide variant, we look for four. That increases sensitivity a lot, you know? That's why I’d seen Dr. Garon mention was the test that our friend Dr. Watson does a lot of that in increasing the single nucleotide variant. And this is the PhasEd. You know how you increase based on that. Unfortunately, because I have to do the negative—I need to win, okay? These are the ASCO guidelines. This is coming this month or next month. This is the ctDNA testing in solid tumors and lymphoma: 2025 ASCO guidelines.  This is a public draft that ASCO put last month. And they want your comments. I sent a bunch of comments against this, because I'm in favor really to use MRD. I don't know what is the final product, but if you see what is in the website, they say ctDNA testing should not be offered if the results of the testing cannot be applied to clinical decision-making outside of a clinical trial. So, basically, if you read the five guidelines, we should not be offering ctDNA outside a clinical trial. I think the guidelines are too radical because, as we were discussing with Dr. Garon, there are areas that we can try to intervene. It's better to do sooner or later, because the other problem that I see is how many years our patients have to wait. You know, this is not standard of care. In three years, we'll tell you. A lot of my patients won't be alive in three years. The best example is the oncotype, the breast cancer. It took 15 years for oncotype to reach the ASCO plenary session. Like, 15 years that the test was available, but we had the same discussions. “Oh, we need to randomize the study. There’s not enough patients. It’s not prospective.” For 15 years, most of the clinicians in the community, you make your decision. You use it, you don't use it. You use it, we don't use it. Finally, after 15 years, we had information. And in the ASCO plenary, they put the oncotype. And now, it's a standard of care. But the patients cannot wait 15 years, you know. So, that's why I am a very academic, I'm a scientist, yes. But the patients cannot wait if there is a technology that can improve their care in their favor. So, that's— but anyway, today, I don't know what would be the final guideline because it's coming soon, but so far it doesn't look good.