Kim Thiboldeaux 00:08
Welcome to the Cancer SIGNAL, a new podcast presented by GRAIL. Where we’ll discuss the origin and promise of multi cancer early detection. The science behind the test, and insight into how this technology has the potential to shift the cancer paradigm. You may have heard about Multi Cancer Early Detection a new way to detect cancer early through a simple blood test. Current guideline recommended screening tests save lives, however, they screened for just five cancers in the US. Most deaths from cancer occur due to cancers we are not even looking for. This is the big idea behind multi cancer early detection technology to transition from only looking for individual cancers to also looking at individuals for cancer, GRAILs next generation sequencing technology was developed within Illumina, and was spearheaded by Dr. Richard Klausner, who directed the National Cancer Institute from 1995 to 2001. The research he launched at GRAIL was among the largest unbiased exploration of genomic cancer signals and blood ever undertaken. This work is the foundation of GRAILs technology. With us on the podcast today is Dr. Richard Klausner, along with Dr. Josh Ofman, who is president at GRAIL. Welcome to the show, gentlemen.

Dr. Rick Klausner 01:27
Thank you.

Dr. Josh Ofman 01:28
Thank you for having us.

Kim Thiboldeaux 01:30
I’m gonna start with you, Josh. Let’s start with the basics. What is multi cancer early detection, sometimes referred to as MCED or M-CED, can you speak to us about how it works?

Dr. Josh Ofman 01:42
Sure. Well, maybe I’ll start with why we think multi cancer early detection is so needed. You know, as you know, we’ve been fighting a war on cancer for 50 years now. And it’s not a war that we’re winning. And that’s because we’re finding most cancers too late. And to the point that you just made, we are stuck in this paradigm of looking for cancers, one at a time. And currently, we have about four to five screening tests that are used to find these individual cancers. And so we’re suffering from this classic streetlight problem where we’re looking over here under a streetlight for these four or five cancers, but all the cancer deaths, about 70% of them are happening over there in the dark, where we’re not even looking. And so the rationale for a multi cancer early detection test is that if we ever hope to really bend the cancer mortality curve, we need to find much more cancer in the population. The current 4-5 screening tests are only finding about 15% of the incident cancers in elevated risk individuals over the age of 50. That’s not going to cut it, that’s just not enough. So by using multi cancer, early detection, or tests that can look for many cancers at once, we can dramatically increase that cancer detection rate. The second reason is that we don’t get to choose the cancer we get. If I could choose what cancer I would get, I would choose colon cancer…I know how to find it, I know how to look for it. And I know how to get it early, even before it becomes cancer. So unfortunately, I don’t get that choice. So we need to be able to look at individuals for their cancer that they’re going to get rather than just looking for individual cancers. And then when I did get my colonoscopy, I felt pretty good about myself. But I failed to remember that I was 10 times more likely in that moment to be diagnosed with a totally different cancer than colon cancer. And that’s the big idea. So we have to make this transition from looking for individual cancers to looking at individuals. And the other reason is that, we can’t, just imagine for a minute a world with five more single cancer screening tests, or 10 more single cancer screening tests, we will not single screen our way out of this problem. For any individual if you had 10 single cancer screening tests, the false positive rate for an individual will be well over 70 or 80%. That’s not tenable. So we now know that we can find common shared signals by looking at genomic signals in the blood, and that’s what GRAIL has developed. So our multi cancer early detection test is looking at, in the blood, DNA in circulation, looking at the methylation pattern, which means, you know, the methyl groups are these little molecules that attach to the DNA and turn genes on and off. And they’re a hallmark of cancer. And you see it across many, many cancers these same hyper and hypo methylated regions of the DNA, and so we can train a machine learning classifier to identify a cancer signal from a non cancer signal by looking at these fragments of DNA. And by looking at these methylation patterns. And we can do that by looking at that shared signal. And then if there’s a shared signal seen, we can then localize that signal to exactly the tissue or organ where that signal came from. So you get a cancer signal detected, and a predicted location of pancreas or ovary or breast or lung. And so we’ve been able to detect over 50 different types of cancer by looking at this shared signal, and that number is likely to increase over time, and do it with a simple single blood draw.

Kim Thiboldeaux 05:44
It’s a it’s a great explanation, Josh, really helpful. You’re harkening back to my sixth grade science class. I appreciate you laying out some of that technology. Rick, let’s go back to the beginning a little bit. Could you share a little bit about the origin and history of this technology? How did we discover this technology?

Dr. Rick Klausner 06:04
Yeah, the origin story of GRAIL is a very interesting one. It really began almost 10 years ago at a company called Illumina, which is the major sequencing machine company that’s learned to very accurately, precisely and sensitively sequence DNA. And at the time, there was a very interesting new molecular pregnancy test, a blood test that can detect very accurately whether an early pregnancy, whether the fetus had an abnormality in chromosome number. This test is called NIPT for non invasive prenatal test. And at the time, this had just been introduced. Illumina had performed about 150,000 of those tests. And there was a wonderful pathologist working at Illumina, named Meredith Miller, who was reading those, all those test results. And Meredith noticed that of the 150,000, there was about a dozen that just had a weird signal. It’s as if the test didn’t work, it was just a screwy signal. And Meredith wondered whether that screwy signal meant something possibly she suggested, could these women, healthy pregnant women, possibly have cancer? Meredith and I knew each other, and she called me and said she had this really weird data, could she bring it and show me, and then she did. And I agreed with Meredith. In fact, I was much more convinced that that signal could only be cancer, there was something about the peculiarity of that signal, that to me, was absolutely unique to the type of genetic and genomic changes that characterize cancer. And that was the birth of the idea of GRAIL. And interestingly, what happened, those women we were able to, to track down through their physicians, almost all of those women. One of whom had recently been, as I recall, diagnosed with cancer. All the rest of whom, the doctor said there’s no evidence they had cancer. And after being convinced to bring those women back in, most of them, if not all of them, proved to have cancer that they didn’t know about. And that was really remarkable. What was remarkable about that, is that there were 150,000 other tests that didn’t have it. And that’s really what led me to say, we have to try to do this because one of the enormous problems with cancer detection, is that we see signals that aren’t cancer. That’s called false positives. And it’s a real problem. But because there are 150,000 tests that were negative, it was immediately obvious to me that there couldn’t be very many false positives. And that’s what got me over the edge to say, wow, this may be for the first time, a blood test that if developed further, can actually be the holy grail of cancer, early cancer detection, which is why I named it GRAIL.

Kim Thiboldeaux 09:29
So great. So we got so take us from that moment of that discovery to the founding of GRAIL to sort of where we are today.

Dr. Rick Klausner 09:36
Well, you know, that created the possibility that that this could work. But in fact, those early tests, the NIPT was never going to be adequate for this. It wasn’t sensitive enough. We didn’t know if it was good for all cancers. But we knew that it said that there was a principle that there was a signal in blood that could detect cancer. When people didn’t know they have cancer. And we laid out four criteria, some of which Josh has alluded to, that we’d have to successfully master, if we were going to turn this into a useful test. One, it had to be sensitive to early stage cancer, cancer that was still localized, so that it could potentially be curable. That’s the idea of early detection. Early means cancer that was still localized before it had spread. Two, it had to detect almost any cancer, but we had to be able to discern in the signal where that cancer was from, or else, you know, what would you do with the signal, you had cancer someplace you didn’t know where to look? So we had to know which cancer. Third, as I said, it had to have a very low quote, false positive rate, meaning that if there was a signal, the chance that that signal was not from cancer had to be very low. And finally, what we hoped is that this signal actually was a signal coming from cancer we cared about. And this is something often people don’t realize there are cancers that we actually don’t care about, that are not going to kill you. They’re not going to. And, and the problem with some early detection is not the failure to diagnose cancer, but the overdiagnosis of things that we call cancer, but actually, we don’t care about and that would cause a tremendous amount of problems. So those were those four criteria. And we set out to begin what turned out to be a multibillion dollar path of doing scientific, technical and clinical development to actually check off those four boxes. Did we have a test that did those four things? And over about four years, we convinced ourselves and others that, yes, we had such a test. And that’s what the GRAIL test is.

Kim Thiboldeaux 12:00
Terrific. Let’s, um, Josh. So why don’t we… Why don’t we come to the current moment, I think our listeners would love to hear a little bit more about the progress that you’re making at GRAIL with multi cancer early detection. So, could you give a brief overview of GRAIL’s clinical program? For example, I think folks would be interested to know how many people you have in trials, obviously, we’re talking about some big, you know, populations here. So could you give us a quick snapshot, Josh?

Dr. Josh Ofman 12:25
Sure. And you know, one of the things that…that Rick did when he founded GRAIL was he made sure it was well capitalized, because he recognized that there was going to be a tremendous need to really rigorously and systematically, and in an unbiased way, search for the best way to detect these cancer signals, and then validate them extensively in large population based clinical studies. So I thank Rick and the early team, for establishing that architecture, and what has become of that is GRAIL has probably launched what is thought to be the largest clinical genomics program linked with clinical data ever assembled. And so GRAILs clinical program consists of numerous studies now that encompass well over 300,000 individuals in a linked database. And that includes, you know, experimental studies that tested head to head the different ways of detecting this signal. And that’s how GRAIL landed on this methylation pattern recognition approach as the best way. And then they validated that three different times in observational studies, case control studies, and then recently validated again in a large interventional trial in the United States called PATHFINDER. And the results, the final results of PATHFINDER will be presented in September had the ESMO meeting. And the interim results really validated the very low false positive rate and the high positive predictive value of Galleri, our Galleri tests, in a in a real world interventional study, the only one of its kind ever done. And, and then we’ve also launched what is considered the largest randomized clinical trial conducted for multi cancer early detection, and one of the largest ever conducted in cancer screening. It’s being done in partnership with the UK’s National Health Service, and it is the UK NHS Galleri trial of 140,000 adults over the age of 50 being randomized to standard of care screening versus standard of care screening plus Galleri, and we’re following people for three years of Galleri tests and GRAIL has decided to use scientifically accepted and very well validated Intermediate endpoints for this the UK is goal is to reduce the amount of late stage cancer that they’re diagnosing in the population. And in discussions with scientists, statisticians, academicians and oncologists, that intermediate endpoint of stage shifting to earlier cancers from later stage cancers is the intermediate endpoint that we’re measuring in that trial. Because as you know, doing mortality endpoints will take more than a decade. And, you know, we have a sense of responsibility and a great sense of urgency to address the over 600,000 lives that are being lost every year to cancer today.

Kim Thiboldeaux 15:45
So to follow up on that, Josh, if we’re talking about that sort of timeline, and where we are in this continuum, I’m sure listeners would like to know, is the Galleri test on the market? Is it approved by the FDA? Is my insurance going to pay for it? Is Medicare gonna pay for it from my mom? You know, where are we with those important sort of policy and reimbursement components?

Dr. Josh Ofman 16:07
Great question. So here’s where we are. GRAIL is in a breakthrough designation with the FDA, and we are doing a modular submission of which that has already begun. And we’re probably a couple years away from an FDA approval. Obviously, the amount that we need to wait for some of this evidence from the UK trial and some of our other studies that we’re conducting to finish. And we’ll get more and more evidence to the FDA, and I think we’re on a very productive path there. So until FDA approval, we don’t really expect broad coverage and reimbursement from the big national payers, we did launch Galleri as a lab developed test, in accordance with applicable laws, CAP, CLIA certified certified by New York State Department of Health, for clinical validation. And once we at GRAIL were comfortable that we had enough clinical validation for Galleri, we wanted to put it into the market as a lab developed test. So it has been in the market now since last June. It’s got great momentum in the market. And one of the benefits of being in the market is enabling us to collect a lot of real world evidence about how the product performs in actual clinical practice at scale, and how doctors are using the signal origin predictions to work these cancers up and the kinds of cancers we’re finding and seeing. And we can use that to help us train future versions of our classifiers and machine learning, but also for our FDA submission. And so that’s really the benefit of doing it. And thus far, what we’re seeing in the real world is very reassuring, and very similar to what we’ve seen in all of our studies.

Kim Thiboldeaux 17:56
Great and the reimbursement piece. Talk a little bit more about that, Josh.

Dr. Josh Ofman 17:59
Yeah, so we do have some agreements now with some very progressive payers Medicare Advantage plan, commercial health plan in the Northeast, and we’re in discussions with some others. But right now, it’s a self pay test, with the exception of self insured employers who are paying for the test. And we have dozens of contracts and partnerships with large self insured employers. And we have many partnerships with health systems as well, who are helping to cover some of the costs of the test. So the test is about $949, which is retail. And some of the big customers get, obviously, better pricing than that. But if somebody wanted to walk into their doctor’s office and get Galleri today, it’s a prescription only test. So the doctor has to think you’re at elevated risk of cancer, order the test, and then it would be about $949 today, and we have line of sight to get those costs down.

Kim Thiboldeaux 18:58
And line of sight towards some better reimbursement?

Dr. Josh Ofman 19:00
Absolutely. We think it’s gonna take time, the payers are gonna want to see a lot of real world evidence and clinical utility data. In other words, you know, how is the test impacting physician decision making and patient outcomes as it relates to the stage of cancer. So as more data emerge, you know we’ll satisfy those requests from the payers. And obviously, when FDA approval is there, we think the payers will really come around. As it relates to Medicare, as you know, Medicare by statute is not authorized to pay for a multi cancer early detection test at all in fee for service Medicare. And so there’s legislation currently, that’s been introduced that has very strong bipartisan and bicameral support. And once that is passed, which we’re optimistic about, it gives Medicare the authority to put a process in place where they can provide payment and coverage for MCED tests.

Kim Thiboldeaux 19:58
Great. Thanks, Josh. So Rick, we, you know, we were all diligent about trying to get our mammograms trying to get our colonoscopy, we just changed the screening age for colonoscopy from 50 to 45, and talk about these five tests. So does this technology, does it in some way replace or change those screening guidelines that are in place, change the recommendations at all?

Dr. Rick Klausner 20:22
No, not at all. The GRAIL test, at least for now, and probably for quite a while, will be additive to those tests. And as Josh pointed out, whenever you go for one of those tests, at that moment, for anyone, the probability that you have a cancer at that moment, that’s not the cancer that you’re screening for, is much, much higher than the probability of having the cancer that you’re screening for. That said, those screening tests are variable in their, in their, you know, you know… colonoscopy is really fantastic and picking up cancer, as is cervical cancer screening. Lung cancer screening, and breast cancer screening, you know, those technologies are less good, but they should be followed, and the GRAIL test is to be added to it. Let me just perhaps comment on controversies around this test, because there are, and explain why there are controversies. So, as we said, the premise of early cancer detection is the idea that cancers start very localized, and gradually grow and eventually spread. And that the ability to cure a cancer when it’s very localized and early, just by surgery or radiation is high. And once cancer is widely spread, despite all the advances, and there are advances in cancer therapy, still, that’s where most people die from cancer. And the idea of early cancer detection is based on this progression, from early stage to late stage, with the idea that if you catch cancer early, you’ve shifted, we call that stage shift, we shifted the stage at which it’s diagnosed. And that’s what we’re so far we’re measuring with the study that Josh talked about in the UK with the National Health Service. But the question is, and it’s a real question, is it actually true that if you shift the stage at which you discover cancer, do you decrease the ultimate mortality of that cancer? And that’s controversial. How do we know that you just don’t have, know that you have cancer earlier, but you’re still going to die at the same date you would have. Now in every cancer early detection that’s been studied for this, stage shift has been associated with saving lives. But rightfully, rigorous scientists ask is that going to be true for detecting it in this different way? and for detecting cancers that we’ve never done those studies. And that’s the rub. So while it’s incredibly reasonable, as we’ve done to presume that stage shift of the detection of cancer will save lives, proving that is important. It’s important to GRAIL, it’s important to the whole world. Our view is, is that the evidence that stage shift from everything we’ve done so far, does predict improved mortality, makes us feel that it is reasonable for people to take such tests, but to make sure that over time, GRAIL, and others are following all those people to collect the data that will take much longer to detect to collect that ultimately proves for each cancer, that early detection will save lives. And that’s where the controversy is.

Kim Thiboldeaux 24:10
Understood, understood. Gentlemen, we’re getting to the end of our conversation. I will say right now, I hope you both come back and continue to update us on the amazing progress that’s happening. But I want to give you both a chance to weigh in, as we approach the end of the show. Is there anything listeners should know about multi cancer early detection that we haven’t discussed here today? You know, closing thoughts about this. Rick, I’ll start with you and then move over to Josh.

Dr. Rick Klausner 24:34
Well, again, when I had the idea of starting this company, and called it GRAIL, because early detection of cancer is one of the holy grails of cancer research. And I personally believe that moving from one by one, looking for cancers, to looking at any, perhaps all cancers at once, is going to have the positive ability of solving that holy grail of making sure that every individual has the opportunity if they are developing cancer, for that cancer be discovered early. And you know, in my 40 years of being in this world, I’ve never felt so intrigued, and so encouraged that this is not just theoretical, because of this new genomic technology, we now have a real possibility to changing the face of cancer.

Kim Thiboldeaux 25:32
Exciting, exciting! Josh, closing thoughts, please.

Dr. Josh Ofman 25:35
Just yeah, the only reason we’re having this conversation is because of this tremendous convergence of advances in human genomics and AI and machine learning. And we do have this incredible opportunity. And, you know, the fact that we’ve developed an assay like this, that minimizes the two most important harms, you know, false positives and overdiagnosis of indolent cancers, is quite an accomplishment. And I think that while there are outstanding questions, as Rick postulated and posed, we just feel a great sense of urgency because, you know, from 50, the last 50 years of fighting this war, we’ve still yet to define for most solid cancers, let alone hematologic cancers, the natural history of disease and what early detection really accomplishes for outcomes, and we can’t wait for that. And if we do it one cancer at a time, it’s just not going to be a tenable world. So, multi cancer early detection is the new front in the war on cancer.

Kim Thiboldeaux 26:43
Gentlemen, thank you both Dr. Josh Ofman, Dr. Richard Klausner. Thank you to our listeners for joining us today for The Cancer SIGNAL. Subscribe to learn more about the promise of multi cancer early detection. Thank you.

Drs. Josh Ofman and Rick Klausner simultaneously 26:56
Thank you

Important Safety Information
The Galleri test is recommended for use in adults with an elevated risk for cancer, such a those aged 50 or older. The Galleri test does not detect all cancers and should be used in addition to routine cancer screening tests recommended by a healthcare provider. Galleri is intended to detect cancer signals and predict where in the body the cancer signal is located. Use of Galleri is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.

Results should be interpreted by a healthcare provider in the context of medical history, clinical signs and symptoms. A test result of “No Cancer Signal Detected” does not rule out cancer. A test result of “Cancer Signal Detected” requires confirmatory diagnostic evaluation by medically established procedures (e.g. imaging) to confirm cancer.

If cancer is not confirmed with further testing, it could mean that cancer is not present or testing was insufficient to detect cancer, including due to the cancer being located in a different part of the body. False-positive (a cancer signal detected when cancer is not present) and false-negative (a cancer signal not detected when cancer is present) test results do occur. Rx only.