Good day everyone. Welcome to the GRAIL ASCO 2026 analyst call. After the speaker's remarks, there will be a question and answer session. If you'd like to ask a question during this time, if you have joined via the webinar, please use the raised hand icon, which can be found at the bottom of your webinar application. At this time, I'd like to now turn the call over to Bob Ragusa, Chief Executive Officer. Please go ahead, sir.
Thank you for joining us this evening. We're excited to be hosting this call from the American Society of Clinical Oncology annual meeting, where we presented the results from two of our large interventional trials this weekend in scientific forums. I'm joined on the call today by Dr. Josh Ofman, our President and CEO-Elect, Harpal Kumar, our Chief Scientific Officer, Andy Partridge, our Chief Growth Officer, and three leading physicians in the MCED space, Dr. Mylynda Massart, Dr. Nima Nabavizadeh, and Dr. Eric Sue. With that, I'll now pass it over to Josh.
Thank you, Bob. As many of you know, GRAIL was founded over a decade ago with the vision of reducing the burden of cancer through population-scale, multi-cancer early detection screening. The goal of cancer screening is really to find cancer in individuals before the cancers have spread, when interventions are more effective and are potentially curative. When we find cancers before they metastasize, outcomes are improved, treatments are less toxic, costs are lower, and the entire experience for the patient, their families, and their caregivers can be meaningfully improved. Unfortunately, today, there's absolutely nothing acceptable about the status quo in cancer screening. Most cancers are simply not screened for at all. In the U.S., we find about 14% of cancers with our current screening programs, and 70%-80% of all the cancer deaths are from cancers that we are not looking for at all.
Finding more cancer earlier, before metastatic spread, can make a meaningful difference in cancer control, in patient outcomes, and the public health. This is not the type of situation that warrants extreme conservatism. It warrants urgency, action, and groundbreaking technology that can make a difference and that can be implemented safely. The results of our randomized controlled NHS-Galleri trial of 140,000 individuals were presented Saturday morning by Dr. Charles Swanton, and the results of our 35,000-patient PATHFINDER 2 study were presented this morning by Dr. Karthik Giridhar. The results of these studies demonstrate the many clinically meaningful benefits that Galleri has to offer for population health. We now know that across these studies, Galleri has detected more than 150 distinct types of cancer, much more than the 50 that we identified with our original study. This is truly remarkable.
The NHS-Galleri study is the first time any MCED has demonstrated the ability to generate a stage shift in how cancers are detected. This is truly a historic moment. Additional data points from the study, such as an increase in cancer detection rates and a decrease in emergency presentation, add substantially to our clinical utility evidence base. In fact, the NHS-Galleri randomized controlled trial, in that study, Galleri found more early-stage cancers than all screen-detected cancers found in the National Health Service's screening program in the control group. Groundbreaking indeed. In addition, performance metrics such as PPV and safety in both studies continue to be strong and consistent across all populations and all of our other studies. We're extremely proud to share these data with you all.
I believe that with the rapidly evolving treatment landscape, combined with the paradigm shift of MCEDs being added to standard of care screening, that we have the opportunity to actually eradicate the scourge and human toll of metastatic diagnoses in our lifetimes. These data that you're going to hear about tonight are the most significant advancements toward that goal that we have ever seen. I'll now pass it to Harpal to walk through the findings. Following the data presentation, Andy will lead a panel discussion with our physician experts. Over to you, Harpal.
Thank you, Josh. First of all, a huge thank you to the patients, physicians, and institutions that participated in these studies. It really is an incredibly exciting time, and there's a lot of data, so I'll get right to it. As Josh mentioned, we read out two large studies this weekend. The NHS-Galleri trial, the first and only randomized control study of an MCED test, was designed to demonstrate population-level impact through the reduction of late-stage cancer diagnosis and increased cancer detection within England's National Health Service. The trial evaluated annual screening with a Galleri test in addition to standard of care screening over three years in more than 142,000 demographically representative participants aged 50 to 77, compared to standard of care screening alone. The PATHFINDER 2 study is the largest MCED interventional study in North America in an intended use population with no clinical suspicion of cancer.
This study evaluated performance of a single MCED test in a population of approximately 35,000 individuals aged 50 and above. These studies add further to the broad evidence we've generated for Galleri. Yesterday morning, the results of the NHS-Galleri trial were presented by Dr. Charlie Swanton. NHS-Galleri is the largest, first, and indeed only randomized controlled clinical utility trial of an MCED test to date. Approximately 142,000 individuals participated in the study. Consented participants aged 50 to 77 years with no cancer diagnosis or treatment in the last three years and no clinical suspicion of cancer gave a blood sample and were then randomized one-to-one into the intervention or control arm at their initial study visit. The MCED test was performed on samples from intervention arm participants, and those with a positive MCED test were unblinded and referred to established NHS urgent referral for diagnostic testing.
All subsequent workup and treatment occurred outside the trial. Participants received routine NHS care and no white glove attention. Cancer outcomes were passively collected using national registry data sets for all participants. Participants were invited to return for two more annual blood samples, and both arms had high retention rates across the three screening rounds. The two arms were very well balanced and generally reflective of the U.K. demographics of the target age group. The trial enrolled from more deprived groups and those with lower education status, which are typically underrepresented in research. Follow-up for the first two rounds were approximately 12 months each. A median follow-up for the third screening round was 17 months. Given the urgent need for improved cancer detection, this screening trial was designed to rigorously assess the benefit of MCED testing in as short a time as possible.
We agreed with NHS England on a pragmatic clinical utility endpoint of a reduction in the combined incidence rate of stage 3 and 4 cancers after three annual screening rounds, with just 12 months of follow-up after the last blood draw. The primary endpoint was assessed as an incidence ratio, which compares the frequency of cancer diagnoses between the intervention and control arms and accounts for different lengths of follow-up times. This was done in a pre-specified set of 12 cancer types responsible for two-thirds of cancer deaths in the U.S. and U.K., and in all routinely staged cancers, including and excluding prostate cancer. The primary endpoint of a reduction in stage 3 and 4 cancers was not met, and we'll talk about what we saw here in just a minute.
As we knew stage 3 and 4 reduction will not be the only relevant measure of clinical utility, the study included several pre-specified secondary endpoints, such as the reduction in stage 4 cancer, increased stage 1 and 2 diagnoses, and MCED test performance. We saw a clinically significant reduction in stage 4 cancers of more than 20% in the incident rounds, an increase of 16% in stage 1 and 2 cancers detected, and strong performance and safety metrics for Galleri. We also evaluated the overall number of cancers detected as compared with the control arm and the impact on incidence of clinically diagnosed cancers and emergency-presenting cancers. With the addition of MCED testing to standard of care screening, we observed a fourfold increase in screen-detected cancers and a substantial decrease in cancers detected through emergency presentation.
The totality of this data provides very strong evidence that adding Galleri to standard of care screening can identify more cancers through screening and enables a stage shift at a population level. Now, we shared back in February that the primary endpoint was not met. If a screening program works, what you would expect to see is a large increase in late-stage cancers detected in the first screening round as you sweep up those late-stage cancers that are already prevalent but undiagnosed in the population. In subsequent rounds, you would expect to see a reduction in late-stage cancers as the effect of the screening intervention becomes apparent. This is exactly what we saw. When we look into the further detail at the data by screening round, we can see that there was a very large increase in cancers detected in the first or prevalent screening round.
As I'll show you in a minute, these were predominantly stage 3 cancers. Overall, there was a 19% increase in stage 3 and 4 cancers during that prevalent round. There was a trend towards fewer stage 3 and 4 cancers in the incident screening rounds, growing to 12% in the third round, but cumulatively not quite enough to overcome the large prevalent round effect. The confidence intervals are broad here and not great enough, as I say, to overcome the large increase in stage 3 and 4 cancers observed in the prevalent screening round. It's important to note, though, that the incident rounds, that is excluding the prevalent round, most closely resemble what we might expect in a steady state screening program.
When we separate the stages, we see a substantial decrease in stage 4 cancers, but this was outweighed by an overall increase in the number of stage 3 cancers, particularly in the prevalent screening round. We believe the stage 3 increase was driven in part by a number of stage 4 cancers being shifted to earlier stages, including at stage 3, and the fact that many more cancers overall were found earlier through screening in the intervention arm, while the equivalent cancers may not yet have been diagnosed in the control arm. We'd expect to see more of these as yet undiagnosed late-stage cancers being found in the control arm with longer follow-up. In addition, the trial has revealed just how much undiagnosed and uninvestigated stage 3 cancer is already prevalent in the population before any screening commences.
Finding these cancers earlier means we can start treating those patients with the urgency needed, and in many cases, with the opportunity of curative intent. If we break down the 14% reduction in stage IV diagnoses by screening round, we see that the reduction in stage IV increases with each screening round. As I touched on earlier, the prevalent round detects undiagnosed cancers already present in the population at the time of initial screening, while subsequent incident rounds detect cancers that develop or progress between screening rounds and become detectable. As I mentioned earlier, the incident rounds most closely approximate the likely steady state impact of an annual screening program. Overall, in this pre-specified secondary endpoint, a 14% reduction in stage IV cancers was observed. These results were nominally statistically significant.
In the incident rounds, there is a significant reduction of more than 22% in the second round, reaching nearly 27% in the third. Importantly, while this slide shows the results for the 12 pre-specified cancers, we saw reductions of greater than 20% in the incident rounds for all cancers, which is a remarkable decrease at a population level. The reduction in stage IV cancers is clinically meaningful. While it varies by cancer, for most of the 12 pre-specified deadly cancers evaluated, a diagnosis at stage III improves survival rates dramatically compared to a diagnosis at stage IV. You can see here the survival rates for stage III and IV alongside the reductions that were found in the study for each of these cancer types.
For example, for colorectal cancers, where we saw a 34% reduction in stage 4, five-year survival is 64% at stage 3 compared with around 11% at stage 4. Not shown on this chart, in prostate cancer, we saw a 25% reduction in stage 4 diagnoses, where five-year survival is 97% at stage 3, but only 53% at stage 4. Along with the decrease in stage 4 cancer incidents, we also observed a 16% increase in stage 1 and 2 cancers for the 12 pre-specified cancer types after three screening rounds in the intervention versus the control arm. As you can see, overall, there were about 90 more cancers diagnosed at stage 1 or 2.
A large part of this increase was in colorectal cancer, with the rest split between upper GI, ovary, and heme cancers, with large increases in individual cancer types typically diagnosed very late, such as ovarian, esophageal, pancreatic, and liver cancers. Shifting to test performance, another secondary endpoint, the aggregate performance metrics were robust. Over 3 screening rounds, 1,801 participants or 0.91% had a positive MCED test result, and 937 of those were diagnosed with cancer for a positive predictive value, or PPV, of 52%. The high specificity of 99.55% means a false positive rate of just 0.45%. The negative predictive value was almost 99%. Episode sensitivity overall was around 30% and around 55% in the 12 pre-specified cancers. Cancer signal detection accuracy was greater than 90%. The safety profile is also strong.
Focusing first on false positives, across three screening rounds in the 70,000-participant intervention arm, there were 864 false positives. This means there was a positive Galleri test, but the subsequent work-up in the system did not find a cancer. 303 of these false positive tests were in the first screening round on which we have two years of follow-up. In 54 of these cases, the participant was ultimately diagnosed with a cancer during the course of the study. In cases where the test was called a false positive and the participant was later diagnosed with cancer, the CSO prediction was correct more than 80% of the time. There were a very small number of phlebotomy-related adverse events and no related serious adverse events were reported.
We have always stated that for MCEDs, it's the cancer detection yield that best reflects the overall sensitivity of the MCED in totality as opposed to cancer by cancer sensitivities. The Galleri MCED has the unique feature of a single specificity that we optimize for, unlike single cancer screening tests that optimize sensitivity. In terms of overall cancer detection yield, the addition of MCED screening to existing NHS screening programs led to an approximate four-fold increase in screen-detected cancers. Many of these cancers were detected in stage 1 or stage 2. In fact, more stage 1 and 2 cancers were detected by Galleri than all cancers at whatever stage detected by all standard of care screening in the control arm. This large increase in screen-detected cancers meant an overall 21% reduction in cancers that then needed to be detected through clinical presentation.
Further, the addition of MCED screening decreased the number of cancers detected through emergency presentations by more than 25%. As you may know, cancers detected in the emergency room represent some of the poorest outcomes and most costly cases. Of the 937 cancers detected by Galleri, roughly 70% were in stages 1 to 3, and roughly 40% in stages 1 to 2, and roughly 20% at stage 1. Roughly 60% of the cancers detected have no current screening paradigm, which increases to more than 70% when we consider that lung screening was only just being introduced at that time. In fact, most lung cancer cases are in individuals who are not actually eligible for lung cancer screening. Now, the Ns get smaller for less prevalent cancers, but you can see the breakdown of cancers by stage here.
These findings demonstrate the opportunity for a transformational shift in cancer detection, moving us to a more comprehensive, proactive approach. Multi-cancer early detection provides an opportunity to reshape screening and detect more cancers when there's an opportunity for cure. Now, I'll spend just another minute or two on the data that was presented this morning on our PATHFINDER 2 study. We presented data on the first 25,000 patients from this study at ESMO in October last year, and this morning presented the data from the full nearly 36,000-participant study. In this study, participants with a positive result underwent targeted diagnostic evaluation guided by the predicted CSO. If no cancer was diagnosed during the targeted evaluation, participants received a protocol-dictated diagnostic PET-CT. The study's primary objectives were to evaluate safety and performance of the MCED test in an intended use population.
Participant population was representative across age, sex, race, and ethnicity, which is important as we sought to assess performance of the MCED test in the intended use population. The full results of the study show the positive predictive value of the MCED test was 60.3%. Specificity was 99.6%, and CSO detection accuracy was greater than 90%. The high CSO accuracy facilitated efficient targeted evaluation. Episode sensitivity for cancers diagnosed in the 12 months following the MCED test was robust, especially in pre-specified clinically relevant cancer subgroups, where we saw sensitivity of up to 70%. More than half of the new cancers detected by Galleri were stage 1 or 2, and more than 70% of these have no USPSTF A or B recommended screening. Approximately 70% of the new cancers detected by Galleri were detected at stages 1 to 3, when treatment with curative intent is more often possible.
Overall, six and a half times as many cancers were detected through screening when MCED was used in addition to USPSTF grade A and B screening recommendations, and three times as many when used in addition to A, B, and C screening recommendations. Galleri demonstrated a favorable safety profile. Screening with a Galleri test had a very low false positive rate and a low rate of invasive procedures. 85% of diagnostic procedures were non-invasive. There were five study-related adverse events reported during diagnostic evaluation, and only in those with cancer diagnosis. Anxiety temporarily increased for participants with a positive MCED test and subsequent cancer diagnosis and returned to baseline by 12 months, as has been observed for other screening tests. At the time of the analysis, five study-related AEs were reported during diagnostic evaluation and, as I said, only occurred in those with a cancer diagnosis, and none were serious.
In these data sets this weekend, we saw clear evidence of strong performance for Galleri. Across the two studies, which included almost 180,000 participants together, we see consistent evidence that Galleri's able to detect cancers that standard of care is not finding today. This is the first demonstration of clinical utility by a stage shift for an MCED test. In a randomized study, we demonstrated a greater than 20% reduction in stage 4 cancers, a double-digit increase in stage 1 and 2 cancers, and a 25% reduction in cancers diagnosed after emergency presentation. In the two studies presented this weekend, we saw that adding Galleri to standard of care increased the number of cancers detected by screening by between four and six and a half times. Today, the standard of care finds only about 6% of cancers in the U.K. and around 14% of cancers in the U.S.
Adding Galleri to the standard screening programs could increase this figure to greater than 50% in the U.S. This is a substantial improvement on current practice and enables detection of cancers that don't have screening options today. The consistent performance that we see between studies enables confident real-world use of Galleri. Multiple studies have now demonstrated a very low false positive rate and a high PPV in intended use populations. The high accuracy of Galleri's cancer signal origin results enable efficient patient-centered care. The Galleri multi-cancer early detection, or MCED test, which identifies a shared cancer signal, has detected over 150 distinct types of cancer, including many deadly cancers that currently lack screening options, such as pancreatic, ovarian, liver, and bile duct cancers.
The Galleri test is the only MCED test clinically proven through a randomized controlled trial to increase earlier cancer detection and reduce stage 4 diagnoses, enabling more patients to have curative treatment. The totality of this data adds to the growing body of clinical evidence for Galleri. We are really excited about this data and the impact it shows that we can have on cancer care. With the addition of a simple blood test to standard of care screening, we now have the opportunity to reduce metastatic cancer diagnoses, enabling many more patients to have the opportunity of treatment with curative intent, as well as the associated reduced financial burden, reduced toxicity, and reduced emotional burden on patients and their families. I'll now pass it to Andy to introduce our physician participants to discuss this data.
Thank you, Harpal. I'm joined this evening, as Bob outlined, by three physicians, Dr. Mylynda Massart, Dr. Eric Sue, and Dr. Nima Nabavizadeh. I'm going to invite each of them to briefly introduce themselves and describe their medical practice.
Thank you. Good evening. I am Dr. Mylynda Massart, and I am an associate professor at the University of Pittsburgh and family medicine physician at UPMC. I run a primary care precision medicine clinic where I have introduced multi-cancer early detection screening since it was released out onto the market. I would like to pass it off to my colleague.
Thank you. Thanks, Mylynda. Nima Nabavizadeh. I'm a radiation oncologist at the Oregon Health & Science University in Portland, Oregon, and I also lead our early detection clinical research team. Early detection has been a priority for our cancer institute for quite some time, and we have been, I would say, super enrollers on the prospective studies from GRAIL PATHFINDER 2, as well as the REACH study. Furthermore, early detection is certainly important, but it's also important professionally as a radiation oncologist in that we have non-surgical curative treatment options available for patients with early-stage cancers. Certainly, early detection is near and dear to what I do and the patients that I see.
I'm Eric Sue. I'm an internal medicine physician in private practice in Los Angeles. I've now done 1,277 Galleri screenings in three and a half years, and I've had six true positive Galleri tests. I think it's incredible stuff, and I think it's only going to get better.
Maybe Eric, we'll start with you. You're actually presenting on Monday, your experience with the Galleri test in your practice here at ASCO. How long have you been offering Galleri to your patients, and who do you recommend it for?
I only learned of Galleri cancer screening in September of 2022. I only learned of it because one of my patients asked me about it. I'd never heard of it before. We reached out to GRAIL and asked them to present the information to us, and when you hear all of the information that you've heard today, it sounds really incredible. I have to be honest, my first question was, is this going to be the next Theranos, where it's a lot of smoke, but is the technology actually there? Here I am, 1,277 Galleri screenings later with six true positives. I do think we're there. It's something that I like to talk to essentially all of my patients about, that I think everyone deserves to know that something like this is available.
If I'm having a conversation with a young and healthy patient who may not need Galleri cancer screening, but maybe perhaps they would want their parents to consider something like this. It's really a daily conversation that something like this is available. It's a blood test that can screen for over 50 different kinds of cancer. It's being described as a liquid biopsy, as a snapshot in time, where if it's negative, you've got a 99% certainty of not having any of those 50 different kinds of cancer at that moment in time, which can be some peace of mind. It's technically recommended for anyone over the age of 50 because that's when everyone's risk of cancer increases, but particularly if you have a known family history of certain kinds of cancer.
Consider doing it on an annual basis, not as a replacement for any current cancer screening guidelines like annual mammograms for females starting at age 40 or periodic colonoscopies starting at age 45, but it's meant to be as an adjunct to try to give ourselves the best chance at identifying any one of these cancers, most of which we don't have any ways to screen for. If the overall risk of false positives is 0.5%, which is unheard of in the cancer screening world, if you did get a positive Galleri test, we now hear that the positive predictive value in actually meaning you have cancer is 60%.
I tell patients that a positive test doesn't mean you have cancer, but it certainly raises the question, and that a positive test tells you what kind of cancer, with now a 91% accuracy, and it tells you where to look. If you take that look and you don't find anything, maybe it was a false positive, and under that scenario, the plan is to repeat the Galleri screening one to two months later, which then the company pays for. If it's positive again and you look for cancer again and perhaps identify something, then that first test appears to have been a true positive, but may have been at a pre-clinical stage where the conventional studies we have available to detect cancer couldn't find anything or shortly following what we were and potentially at a very early and very treatable stage.
I tell patients I really believe that we may be on the frontier of what we're going to be able to achieve from an early cancer detection standpoint. Fascinating stuff.
Thank you, Eric. I encourage anyone here at ASCO to go and talk to Eric at his poster on Monday. Mylynda, how have you been incorporating Galleri into your practice, and how did you first hear about it and decide to incorporate Galleri?
Yeah. I first heard about it actually when our executive health wanted to implement this testing for their patients. Because it's a new and emerging precision medicine technology, they were a little bit nervous, and so they came to our precision medicine clinic to have additional backup and to have genetic counselors available and clinicians familiar with genomic technology and overall screening. We became very excited to be able to support that project and then also be able to start informing our own patients about the opportunity to have this added to their gold standard USPSTF cancer screening.
In my precision medicine clinic, I do care for many high-risk patients, both not just by age over 50, but by those who are positive for hereditary cancer risk variants, those who have had significant family history but may not have a genetic risk that's been found, and other individuals with exposures or chronic illnesses that make them at higher risk for cancer. This has been a great adjunct that we have been able to educate our patients about. We normally tell them about the opportunity if they're a new patient and we're taking that family history for the first time and reviewing what type of screening they are current with. Sometimes we will bring it up if a patient comes in for an appointment and shares a new diagnosis in the family or just a concern in general about cancer.
Always with every annual wellness visit, where that's where primary care always is addressing any proactive health screening, including cancer screening at relevant ages.
Thanks so much, Mylynda. Nima, as principal investigator in the PATHFINDER study, you followed a large number of patients on Galleri. What have you learned through this process, and any specific patient examples come to mind?
Yeah, absolutely. Like I mentioned, we've been enrolling on PATHFINDER 2, and the REACH study and have nearly worked up 100 patients with signal positive findings at OHSU. Given our clinical trial system, those are largely centralized within our clinical trial team, and we have plenty of examples here. I was invited just a couple of months ago at the American Association for Cancer Research to speak on this topic. I was invited by the BloodPAC Consortium to speak on this topic. The message that I was trying to relay to the packed room was the strong value in the cancer signal origin result that comes from the signal-positive finding.
I was pleading to the investigators and the other test developers in the room to really work on this because my experience working with the Galleri test and seeing the CSO finding is that it's incredibly helpful. I'm a radiation oncologist. I examine imaging all the time. I use it as part of my treatment plan, and indeterminate findings are all over the place. For a patient who has a signal-positive finding and what radiologists may call an indeterminate finding, but then that matches the cancer signal origin, especially with a positive predictive value of 60%, it allows evidence for me to sit down with my specialist colleagues to potentially go the extra mile to try to really further adjudicate and identify what's going on with this indeterminate finding.
A good example here is a patient who had a signal positive for a gastroesophageal cancer, they had previously many years ago had a gastric bypass surgery. With the gastric bypass surgery, basically it excludes the bottom portion of your stomach from your esophagus. We provided the cancer signal origin specified workup, which is an upper endoscopy, and the endoscopist was only able to access the first third of the stomach or so. It was normal. Before deeming this patient a false positive, we obtained whole body imaging. Whole body imaging with a PET-CT revealed some subtle avidity in the bypass portion of the stomach that was inaccessible with routine outpatient endoscopy. I think in the absence of the cancer signal origin finding, that subtle avidity would've been kind of put aside. Going the extra distance to biopsy that area is a big deal.
I sat down with my gastroenterologist, we looked at the imaging. I explained the cancer signal origin and the PPV of the test. That portion of the stomach was able to be biopsied, but had to be in the operating room under general anesthesia using this very long endoscope that goes into the small bowel and back into the bypass portion of the stomach. It was a biopsy proven gastric cancer, early stage gastric cancer. Without that cancer signal origin, we would've completely overlooked it, and this patient would've presented with stage 4 cancer. Another example is a patient who had an ano rectal signal, and underwent signal positive workup. With that, you automatically go to endoscopy with a lower endoscopy, and that patient came back positive for an early stage anal cancer. This is important because certainly this is a curative treatment option.
Because it was found early stage in an asymptomatic, non-symptomatic situation, this patient is able to receive less radiation, less chemotherapy, much less side effects with fantastic survival. Interestingly, when the colorectal surgeon that I referred the patient to who called me back with the result of the biopsy, he relayed the result, but then his second question was, "How can I get this test?" He was totally shocked by the sensitivity of this test to pick up that early stage anal cancer.
Thanks for sharing your experience with the CSOs. It's something we hear commonly from physicians, also from patients, and of course, this is something that at the FDA advisory panel on MCEDs, was something that the FDA felt was an important component of any MCED. Eric, I want you to think about the current status quo of screening in relation to what we saw both in NHS-Galleri, where we saw four times more cancers identified through screening in the intervention arm compared to the control arm, and also what we saw in PATHFINDER 2. What is this impact to you as both a physician and to your patients when you think about the current status quo?
Sure. When you understand the status quo with five current cancer screening guidelines, we're only able to capture 29% of the cancers that people are dying from, leaving 71% of the cancers that people are dying from that we have no available cancer screening measures for. What really struck me about hearing all of this information that was presented this weekend, when you look at PATHFINDER 1, which is GRAIL's initial real world interventional trial in the midst of the pandemic that enrolled 6,600 patients, they saw a twofold increase in the cancers detected when compared to standard of care. Now we're hearing that with PATHFINDER 2, there was a threefold increase in overall cancers detected when compared to standard of care, and that with NHS-Galleri, we've now seen a fourfold increase in cancer detected when compared to standard of care.
We are literally witnessing the power and potential of MCED testing when performed at scale. We now have evidence showing that annual Galleri cancer screening can reduce stage 4 cancers by year 2 by 22%, and by year 3 by 26%. By shifting cancers away from metastatic presentation and closer to earlier stage detection, we're creating so many more opportunities to intervene when curative treatment may still be possible, and most importantly, where the opportunity to reduce cancer mortality is the greatest. That's, I think what's really stood out to me this weekend.
Thank you, Eric. Mylynda, what were your reflections after seeing the presentations this weekend? What did you find most compelling about NHS-Galleri and PATHFINDER 2 study results?
Yeah. I was really reflecting all weekend after listening to each of the presentations, last night I was really thinking that, as a scientist, I have reviewed this data over the last four years as it continues to emerge and evolve and I have really seen the established scientific validity of this screening. As a primary care provider, my heart has been very heavy for the patients that I have lost over the last 20 years of practice. I now have hope for a different future, and a future where we can actually screen and catch more than just five cancers with an opportunity for treatment with curative intent, which is transformative in my lifespan.
As a patient, I am convinced that I am here today because my melanoma was diagnosed at stage 1 in 2018. I myself have added this to my screening regimen every single year to ensure that I have the best opportunity to keep that going. As a family member, I got to see my own stepmom diagnosed with stage 4 glioblastoma in the emergency room after a sudden onset seizure while she was out for a walk after dinner one night with my brother. He then dropped out of college and took care of her until her passing and never returned back to university. All of this data and reflecting on all of these experiences from these different perspectives truly gives me hope that we will actually see a profound difference in the future for our ability to screen, detect, treat, and support patients and their families from cancer.
Mylynda, thanks so much for sharing those personal experiences. That's what brought all GRAIL employees to GRAIL, and that's what keeps us focused on the mission that we have. Nima, you've heard Eric and Mylynda talk about the decrease in stage 4. What are the benefits for your patients on shifting the diagnosis to earlier stages when you think about this from a radiation oncologist perspective?
Yeah, thanks. It gives them a shot for curative treatment, and that's what people are seeing me in my clinic for. They understand that a lot of these cancers are really aggressive. They're aware of that, they've been told that, all their research shows that, but what patients are looking for is some hope and a shot to cure this cancer. That's really what happens in the stage 3 situation. I see patients in my clinic from the stage 1 situation to stage 4 situation. In the stage 4 setting, largely our discussions are in regards to what can we do to treat your cancer to help with symptoms or improve your quality of life? The conversation is not in the sense of what can we do to cure this cancer.
In the radiation oncology world, we're typically brought in and involved to treat these stage 3 cancers, and over the last decade or so, there have been a multitude of advancements in the stage 3 scenario, particularly with the progression in immunotherapy and the addition of that to standard of care surgery and radiation that has really moved the needle for what was previously thought to be really, really bad, aggressive cancers, a great example of that being a stage 3 lung cancer. The treatment intensity and toxicity, as I mentioned with that anal cancer patient, is far fewer and far less once you're able to bring the stage down from stage 4.
Thank you. Eric, you talked a little bit about the positive predictive value of Galleri. How does that compare to other screening tests that you currently use, and how do you describe the benefits of a higher PPV with Galleri to your patients?
When I was first introducing Galleri to patients, I was working with PATHFINDER 1 information. At that time, the positive predictive value was 43.1%. Oftentimes, people would hear that and say, "So if I do this test, I get a positive test. I have a less than one in two chance of actually having cancer. That's not great. Do I really want to do this test and subject myself to that potential of going down that rabbit hole and not being found to have cancer?" I mention, well, what's the positive predictive value of an abnormal mammogram and actually meaning someone has breast cancer? 4.4%. What's the positive predictive value of a positive Cologuard stool test, which is being used as potentially an alternative to colonoscopies and is fully covered by all insurance and Medicare, in actually meaning someone has colon cancer? 3.7%.
43.1% positive predictive value of a positive Galleri test and actually meaning someone has cancer is an order of magnitude better than what we're doing as standard of care. Now we're hearing with the totality of the PATHFINDER 2 trial data that that positive predictive value is 60%. With NHS, in the prevalent screening round, that the positive predictive value is 58%. Again, an order of magnitude better than what we're doing as standard of care. Nothing like this around anywhere.
Thank you. Mylynda, I'll ask you the last question before we open it up to Q&A. In the U.S. and also in the U.K., a substantial proportion of patients are diagnosed with cancer in the emergency room. In the NHS-Galleri study, we observed a substantial reduction in ER diagnoses in the intervention arm with Galleri. Can you describe what it means to a patient and their family to be diagnosed with cancer in the ER?
Yes. Not only did I share the story of my stepmother, but I am a hospice medical director and have been for 17 years. Seeing patients diagnosed with a very advanced cancer in the ER is incredibly traumatic to both the patient and to their family. They often have very poor outcomes and very little time to make decisions. It's incredibly stressful to make those types of decisions in that environment. In our country, we always think that we need to treat, treat, and that is true if someone has an earlier stage detection. When it comes to presenting that symptomatic in the emergency room, most of the time it's incredibly late stage and diffusely metastatic. There are not great options, and that's when I get called in to meet with those families, and I think it's devastating.
I think more than anything, what I've heard from patients over the years is hope is critical. Not only does early detection prevent those types of traumatic events, but it allows us to finally detect cancer with intent to treat successfully, and that is what hope is all about. That's really a gift.
Mylynda, Nima, and Eric, thanks for sharing your perspectives and really bringing to life what Galleri means in your medical practices and what it means to your patients, and brought to life what these NHS-Galleri and PATHFINDER 2 results mean when we actually implement the Galleri tests within medical practices. Going to open it up to questions on the line. Over to you, moderator, please.
We will now move to the question and answer session. If you have joined via the webinar, please use the raised hand icon, which can be found at the bottom of your webinar application. When you are called upon, please unmute your line and ask your question. We will now pause for a moment to assemble the queue. Our first question comes from Subbu Nambi with Guggenheim. Please unmute yourself and ask your question.
Hey, guys. Thank you for taking my question. Good evening. Harpal and Josh, I want to give you an opportunity to address the points brought up by discussant yesterday regarding two points. One, catching less stage 4 may not improve outcomes, and two, detecting cancers in stage 1 and 2 that are already screened by standard of care, and that catching rare cancers may not be cost-effective. What would be your discussion points?
Thanks, Subbu. This is Josh. Let me take the first, the second one first of the cost-effectiveness. And Again, most of what Galleri finds are cancers that are not detected by current screening. In fact, almost three-quarters of the cancers we find are cancers other than what is found by mammography or colonoscopy or low-dose CT or PSA testing. That's really not an issue. As it relates to cost-effectiveness, we've already demonstrated and published numerous cost-effectiveness analyses that shows that given our current set of assumptions, Galleri is a highly cost-effective intervention. Those are being rerun now with the latest data. We're highly confident that they will remain a very cost-effective intervention, good value for money, and as cost-effective as any of the single cancer screening tests.
In terms of your first question, again, this is a very common thought that it just may not be important to find cancers in their earlier stages. That's very curious to me to hear people say that. Clinical practice, other than for prostate and thyroid cancer, which are very slow-growing, is to aggressively treat all early cancers. That's what happens when they are found incidentally. That's what happens when they are found through symptoms. That is what happens when they're found through MCED screening. It's curious to hear oncologists say things like, "We just don't know if it's of benefit to find cancer early." To me, that raises very fundamental questions about whether it would be ethical to not treat patients with early cancer. I don't believe it is. I think we have to just look at how clinical practice is delivered today.
When we find cancers early, they can be offered with treatment options that very frequently in stage I-III provide the opportunity for curative intent.
Harpal, do you want to add to that?
Yeah, I will just add one point, which is, I think we need to look at the data. The data says it all. I gave the example and I'll quote it again. A stage 4 colorectal cancer has a five-year survival rate of 11%. A stage 3 colorectal cancer has a five-year survival of 64%. I challenge anyone to say that's not meaningful. I fundamentally don't accept the premise that finding that cancer at stage 3 rather than stage 4 is not beneficial for the patient.
And Subbu-
Harpal, I hear you.
Oh, go ahead, please.
No, I hear you. When you cite CRC, people argue that there are better sensitivity tests already out there, why do we need another multi-cancer test altogether, adding to the cost?
I think the fundamental point is because of the situation that we have today, which is that we're only finding 14% of cancers through all of our existing screening programs in the U.S. That leaves the other 86% that are not currently being found through screening. What the PATHFINDER 2 study showed was that we have the opportunity to find 60% of cancers through screening. It's extraordinarily additive. We've been very clear from the beginning that this should be complementary to existing single cancer screening, not a replacement for those. The complementarity is, I think, very strongly demonstrated when we can go from 14% of cancers detected through screening to 60% of cancers detected through screening.
Subbu, just last point is that while we're not suggesting colorectal cancer was used by Harpal as an example of the benefits of finding cancers in earlier stages than in their metastatic state, the survival cliff across most solid tumors is now between stage 3 and stage 4. 10-15 years ago, it was between stage 2 and stage 3. That has dramatically changed due to the treatment landscape evolution. I would also challenge any of the academics who like to say things like, "We're just not sure we should be treating early cancers," to ask any patient who's diagnosed with an early cancer if they would like to forego treatment. They're unlikely to find any patient who would agree to that.
Thank you, Josh and Harpal. I wanted to hear your thoughts on this. Recognizing that reimbursement is predicated on FDA approval, do you come out of this ASCO better or worse with regards to FDA and by extension CMS?
Well, it's a really provocative question. I don't know the answer to that question. I think that we feel that the evidence base has been quite solidified by the data that's been presented at this meeting. Again, the FDA will be looking at our package that we submitted to them, which includes the first year of the NHS-Galleri trial and all of PATHFINDER 2. They're going to be focused on clinical validation and clinical performance. We don't believe that they're going to be particularly focused on clinical utility and stage shift. We do think that CMS and payers will be quite interested in stage shift, and I think you've already heard from Harpal how compelling we think these data are.
Okay. Thank you so much, guys.
Our next question will come from Dan Brennan with TD Cowen. Please unmute yourself and ask your question.
Great, thank you. Maybe just following up on one of Subbu's question. There was a lot of discussion about where the benefit for Galleri is. Obviously, the unscreened cancers screams out, although the data looks encouraging in certainly CRC and lung. I'm just wondering, from the NHS-Galleri data, how would you rank order the unscreened cancers where you think Galleri shows the biggest benefit? I know you've got slides showing stage 1 and stage 2 shift and stage 4 shift as well by cancer types, some interim in that. As a follow-up to that, if in fact the FDA were not to approve Galleri label with lung or CRC, how would that impact the value of Galleri from a clinical utility and a health economic basis?
Maybe I'll take the second question and then give it over to Harpal. On the second one, we have been fairly reassured as best we can that irrespective of what the label looks like, we're going to be able to return every result that we find back to the doctors and their patients. We will continue to find interval colon cancer, interval lung cancer, interval breast cancer. You see that throughout our studies. We don't think the labeling, whatever it may end up looking like, is going to particularly impact the overall value proposition because we will be able to return all those results. As we've stated, we found over 150 different types of unique cancers already through these vast studies. I'll turn it over to Harpal to get through the first question.
Dan, thank you. It's an extraordinarily hard question to answer when you ask me to rank order where I see the benefit. Actually, the reality is we're looking at so many different types of cancer, which have very different levels of aggressiveness, of prognosis, of incidence in the population. To say that an ovarian cancer is more important than a colorectal cancer is more important than an anal cancer is something I struggle with. We want to show benefit across as many patients as possible. I think we've demonstrated that this multi-cancer test really is that. It's multi-cancer and to the point about is it really useful to detect additional colorectal or lung cancers when we already have screening programs? I would make a couple of points, which is those screening programs miss the majority of those cancers.
Colorectal screening in the U.S., fantastically effective though it is, finds about 25% of colorectal cancers. There's another 75% that it's not finding. Lung screening is not available to the majority of people who end up with a lung cancer diagnosis. There is huge complementarity here, and even in breast cancer, we're finding interval cancers between screening rounds that the mammography program misses. I hesitate with the notion of rank ordering. I think there's benefit really across the board here.
Yeah, if I can add one comment, this is Nima. In the state of Oregon, only 10%, and we've looked at this at the Oregon Health & Science University, only 10% of people that are at high risk and eligible for a low-dose CT screening are actually getting it within the state. There's a multitude of factors there in regards to access and stigma. Oregon's a very rural state, and you have to be close to a CT scanner to get these exams. Furthermore, even for more common screening practices like mammograms, very recently, we had a signal-positive breast cancer in a patient who skipped out on yearly mammograms because they were worried about the radiation exposure from the mammogram. The Galleri test here identified the early-stage breast cancer in this patient.
I commend GRAIL in providing these results irregardless of the cancer signal and irregardless of the other screening techniques that are available for these patients, because not everybody's getting them.
Great, then maybe just on the data, just as a follow-up, a two-parter. You mentioned that you think there's going to be a lot of late-stage cancer that are going to show up in the control arm, just given the dynamics of what you saw. I'm just wondering how we might see that come out, over what timeframe. When will that get reported? Will it get reported? Then B, the study was run at three years, and feedback from experts reflected a screening study like this probably needed to be run a lot longer in order to catch the full extent of it.
The assay was improving at year two, was improving at year three. Is there any way to think about at what point it would asymptote? I don't know if that'll be something you guys can do. Obviously, the study stopped, right? This would be all modeled out, but I'm just wondering kind of the trajectory that you saw at year three, what would that imply if we played it out further?
Thank you. On your first question, which is the further follow-up, I think we've said a couple of times now that we want to continue to follow up the NHS-Galleri population for at least another 12 months. We are hopefully close to getting that agreed with the NHS. Assuming we do, that data should be available, analyzed by, I would hope, Q1, Q2 next year. In terms of where and when we will present it, that's still to be determined. That's roughly speaking the timeline that we would expect to have that information on. Your second question, which is we did all this very quickly. We did. As you rightly point out, most screening studies historically have followed up for a lot longer before they report any results. Indeed, most screening studies historically didn't even pre-specify endpoints.
They waited until they had an endpoint before they reported one. We chose not to do that because frankly, it's not a very good scientific way to do this kind of work, and we want to do things properly. Actually, the more important point is that we wanted to get to results quickly because thousands of people are dying from cancer every day. I've pushed my team, we as a company have pushed to get to results as quickly as possible so we can help the clinical community start saving lives.
In the interest of time, please limit yourself to one question. Thank you. Your next question comes from Kyle Mikson of Canaccord. Please unmute yourself and ask your question.
Hey, guys. Thanks for the questions. Multi-part question on it, NHS trial. It does seem logical that there would've been a boatload of cancers detected in the prevalent round, with, I guess, stage 3 being the most abundant by far. If you foresaw or expected this, I think Harpal you mentioned that, did you try to deprioritize or remove the prevalent round from the primary endpoint during those initial kind of trial design discussions? I know it's a tough question, but just more context would be interesting. Secondly, given this round was the most problematic, but it's the only NHS trial piece provided to the FDA, could you try to provide supplemental data from the incident rounds to the FDA? Even though they focus on safety and performance, but they might kind of have to look a little bit at the clinical utility possibly for this. Thanks.
Yeah. Interesting question. The challenge with it is once you pre-specify a primary endpoint, it's really not appropriate to change it when you see the data. I understand the question, I understand where it comes from, it just wouldn't scientifically have been the right thing to do, and we would've been criticized very heavily for doing so. What we've tried to do is to present the results transparently, completely openly, recognizing that that meant that the primary endpoint wasn't met. I think the fact that we're able to show the data in the granular way that we've done so, and showing the difference that the incident rounds make is really the important point here, because people can then see it for themselves and make their own decisions. We think it's profoundly important that we're seeing these substantial stage 4 reductions in the incident screening rounds.
Kyle, maybe I'll add one thing. You heard Dr. Swanton say yesterday that this study was designed almost eight years ago with some assumptions about what we would see in the prevalent round based on the best available knowledge at that time, which was very little. Those estimates were off, and there was just quite a lot more stage 3 cancer than was ever anticipated. Had that been anticipated, perhaps the study would've been designed to have longer screening rounds or things like that, but nobody knew that. To Harpal's point, it would not have been appropriate to have changed anything based on what we had pre-specified. I think Dr. Swanton made that point quite clearly yesterday.
Sorry, just to add one quick comment. It is just worth reiterating, one of the things we learned in this study is just how much undiagnosed late-stage cancer exists in the population. We had no idea that was the case because it's never been studied before. Now we know. It'll give us huge insights into how we think about both the prevalence of cancer, but also what we might do about it going forward.
Kyle, Harpal's point is, whatever the primary endpoint was, doesn't dictate what you actually observe in the trial. To Harpal's point, what was observed in that trial is now being made clear to everybody, and that's what's really important and we think will be the legacy of this trial and of this meeting. Yeah. Go ahead, Mylynda.
Yeah. This is Mylynda. I wanted to just add that as a primary care provider, I think it's really interesting that folks frame this as a failure. To me, I see from the scientific viewpoint that it just means that three years wasn't long enough. When I explain that to my patients, then I might say, "We need to do annual screening for four years to actually feel confident," as opposed to three years, which is not a reflection on the technology or a reflection on the ability to capture cancers earlier, but really a reflection on how we will eventually see population shift. To me, that's still a pretty valuable information that we've learned from the science. Even more excitingly, I get to counter that with even in that timeframe, we may catch four times more cancer and catch cancers that we've never been able to screen for before.
Our next question will come from Catherine Schulte of Baird. Please unmute yourself and ask your question.
Great. Thank you for the question. If I just think about NHS-Galleri, you showed reduction in stage 4, reduction in combined stage III and IV by the third round of screening, an increase in early-stage diagnoses, an increase in overall cancers detected, yet there are still some questions out there about clinical utility. Do you think at some point you're just going to have to show mortality data? This is obviously a very high bar, do you have any plans to evaluate that? Maybe absent mortality data, just what do you think is the metric that should be viewed as the best measure of success for MCED tests, given what you know today? Thank you.
Well, it's a very thought-provoking question, and I'll look to Harpal and our experts to comment as well. I'll tell you that I don't believe a true mortality study is going to ever be done for an MCED. I think while people like to talk about that has been the standard for single cancer screening. I don't believe that's an appropriate standard for a multi-cancer screening test. Underneath that request, the presupposition is that we don't know that it's a good thing to find early cancer, and I just completely disagree with that premise. We know quite a lot about finding early cancer. We've done it for all the cancers that we screen for. We know that it's done in clinical practice every day, and Harpal has already talked about the mortality differences between these different stages that we see at the population level.
I think that study's not going to get done. It's really important to remember that we have agreed to explore mortality in NHS-Galleri, but NHS-Galleri was neither designed or powered to show a mortality benefit. I'm going to let Harpal talk about how we're going to do that in a minute. Your bigger question is what is the right endpoint? I don't think there is a single right endpoint. This is about how do we best address the screaming unmet need we have right now to find cancers in the population, to find more cancers in the population through screening, and to find them at stages that are not metastatic, where people have the opportunity for curative intent. My view is the most important thing we can do in MCED studies going forward is to show a reduction in metastatic disease.
I believe that we are on the precipice of seeing an eradication of the diagnosis of these dreadful cancers when they're already metastasized in our lifetime. These data that Harpal has just presented to you are the best data available to give me hope that that is actually going to happen. I don't think there's any one magic bullet here. I think it's going to be a lot about all the endpoints that Harpal has been describing, but the most important of which will be a pure reduction in the diagnosis of metastatic disease. Harpal.
Yeah. I'm going to agree and disagree with what Josh just said, just for some entertainment value. First of all, I fully agree. You have to look at the totality of the evidence. There isn't one single way of determining the utility of a multi-cancer screening test. I'm not really going to disagree, but what I would say is if I were forced to pick one, I would say the most important thing is to be able to find cancers at a time when we have treatment options available that might be curative. At the end of the day, that is what matters. If we can find them at a stage when the answer to that is yes, that is what's meaningful to patients, it's what's meaningful to health systems, and it's what's important to populations.
Finding cancers before we run out of treatment options, or even better, finding cancers at a stage when we can develop better treatment options for the future. That's what I'm focused on. Having said all of that, yes, as Josh alluded to, we are going to look at different ways of exploring mortality from NHS-Galleri. Some of that will simply be passive follow-up of the individuals, where we'll compare the number of people who have died in the two arms at time points into the future. As Josh importantly pointed out, that's not powered, but we will look at it, and we'll report it. There is another analysis we'll be doing, which I'm not going to describe in detail here, but it's what's called a nested mortality analysis, which we would hope to have sometime in the 2028 timeframe. We'll report on that when we have it.
Our next que-
This is Mylynda again. I just wanted to add, again, also just to this from the primary care perspective. The utility also has to be about feasibility and acceptability, right? If we continue to think that we need to expand cancer screening and include cancers beyond our current five that we're able to screen for, it's not feasible to do that on the single organ basis. As a primary care provider, you would spend all of your time then trying to track down and get patients to achieve their cancer screening, and it wouldn't be acceptable to the patients either. It also would have a dramatic increase in the rate of false positives, which would lead to all sorts of significant consequences. I think we also have to think about the utility in these terms as well.
It's a great point. Maybe one way of reframing that is what is the alternative to using an MCED for population screening? It would be to continue to develop more single cancer screening tests. As all of you have heard us say before, those false positive rates accumulate in individuals. A 50-year-old female who's getting a mammography, a colon cancer screening test, a cervical screening test, and let's say they're a smoker and they get low-dose CT of the lungs, that individual female would have a false positive rate in excess of 40%. No one would ever recommend a test like that to a woman, nor would anybody ever approve a test like that. Imagine a world with five more single cancer screening tests. It is untenable, not feasible, and there would be major safety concerns associated with that.
In our view, there is no alternative to really screening for multiple cancers beyond the five that we have now without an MCED test.
Our next question will come from Puneet Souda with Leerink Partners. Please unmute yourself and ask your question.
Yeah. Hi, guys. Thanks and congrats on completing and presenting the largest trial in early detection. This is a multi-part question. It's rather simple. The first part is really simple. Look, it's an important one in terms of clinical adoption, so asking both management and physicians on the panel. What do you think the reaction and prescription behavior of an average primary care physician of the U.S. was on February 19th when the headline for primary endpoint not meeting came about, versus the detailed data cuts that you're providing today? Would this additional data detail change that prescription behavior versus February? Do you think you have to ask FDA on changing the marketing materials since you're already engaged with them? Lastly, for Harpal and just maybe for Josh, you've learned a lot through this trial.
What would you do differently if you had to redo this trial again? Thank you.
Thanks for your question. I'll take the first one. As I outlined on our last earnings call, we are certainly hearing from physicians that they're getting a lot of questions from patients following not just our press release, but some of the negative headlines that appeared in some of the media. We haven't been able to address those questions that physicians have had in a really meaningful way. I'm personally excited that we're going to be training all of our teams, both our medical teams and our sales teams, on the detailed data that we presented here at ASCO on PATHFINDER 2 and NHS-Galleri, because going forward, we're going to be able to answer those questions. As you've seen, the data are simply remarkable, and we believe they're going to be transformative.
I think they're going to have a positive impact on prescribing going forward, but I really shouldn't be the one speculating on that. We have three physicians on our panel now. I'm going to ask them what has been their experience with their patients following the press release and negative media coverage, and what do each of you think is going to happen going forward now? Eric?
Sure. I got plenty of emails and phone calls following the headlines three months ago. "Cancer screening fails major trial." I thought they were really unfortunate headlines, because I think what they threatened to do is render the entirety of this massive landmark, never-before-tried trial as completely meaningless, to render everything else GRAIL has done in the last five years as completely meaningless. What I tell patients and colleagues is that what the NHS trial has shown, and it can tell them even more based on this weekend, is a greater than 20% reduction in stages 4 diagnoses by years two and years three. That saw a fourfold increase in overall cancer detection rate when compared to standard of care. A substantial increase in stage 1 and 2 cancers at 16%, when those cancers would have otherwise gone undiagnosed. None of these are trivial things.
These are all things we should want in a cancer screening tool. I would say that for physicians who are already ordering Galleri, I don't think that this data is going to stop them and prevent them from ordering it more. I think that there are plenty of questions about other competitors in the space who are oftentimes marketing to physicians and to consumers alike.
I don't think have any real-world interventional prospective trials that prove what they are showing in their case control trial data actually works in the real-world intended patient use population. That's everything that GRAIL has done in the last five years. I remained hugely optimistic about the potential of multi-cancer early detection and GRAIL just submitting their pre-market approval application to the FDA on January 29th. Soon thereafter, the president signing into law the Medicare Multi-Cancer Early Detection Screening Coverage Act, establishing a pathway for Medicare reimbursement if and when multi-cancer early detection testing becomes FDA approved. We're heading in a direction where this may become recognized as a valuable tool when we understand, again, that the status quo is far from perfect. Potentially covered by Medicare, after which private insurance companies might follow along as they ordinarily do.
This may become much more widely available to everyone that we believe deserves to have access to something like this. Incredible.
I guess I'll add. I think for anybody to look at this trial and say that it was a flop is completely disingenuous, and they're not paying attention, and they're reading a single sentence from the primary endpoint. In my practice, having worked with the technology, I know it's been working. I know I've picked up early-stage cancers that patients wouldn't have otherwise known about. The richness and the granularity of the data in regards to the incidence and prevalence rounds of the screening are quite remarkable. Just so excited to see another year or two or follow-up in this because really, the data is actually incredibly encouraging. I think the challenge for GRAIL is how to disseminate this information to the lay press in a lay way and who to do that with.
Because a trial failed is probably more clickbait than a trial failed. There's actually some really encouraging signals that we need to wait for and look at that I think is more challenging.
Yeah, I completely agree with my colleagues, and I think all that I would add is it's the wrong headline. It's just absolutely the wrong headline, and it doesn't do service to our patients and our communities and our populations to not focus instead on all of the incredible science and things that were learned from this trial. The opportunity to catch four times as many cancers as we've been catching with standard of care thus far.
Thank you. Finally, on the question about the FDA, right now we're not thinking about changing any of our materials prior to the FDA approval. Obviously, when the FDA does approve Galleri, which we obviously hope it will, we will have to re-look at what the label is and what our marketing materials are. We wouldn't do anything like that until at that time. Harpal, I'll ask you the final question he asked about what have we learned, and is there anything we would've done differently?
Well, we've learned a huge amount, and we're continuing to learn, and we will continue to learn because this is an enormous data set. We've definitely learned some things. We've learned that, as I touched on earlier, there's a huge amount of undiagnosed relatively late-stage cancer in the population. That's quite a sobering insight, actually, that we've discovered from this trial. Now that we know that, now that everyone knows that, I think that will have implications for if there are future trials, how they should be thought about. I'm not going to say we should've done the design in a different way, that it wouldn't be appropriate to do that with the benefit of hindsight. What I would say is that a trial has to be designed in the context of what you know today.
What we know today is that the treatment landscape is very different now from what it was 10 years ago. We can treat many stage 3 cancers now, which wasn't possible 10 years ago. The fact that we can do that means that actually finding cancers before they reach stage 4 is a really fantastic opportunity for transforming cancer outcomes.
That is the primary endpoint for the Medicare REACH study, which was designed just a few years ago. It's much more of a focus on remediating stage 4 disease and finding cancer before it's metastasized. Hopefully that answers all your questions.
Our next-
I think we have time for one more, Alex.
Our next-
Thank you.
Our next question will come from Kallum Titchmarsh from Morgan Stanley. Please unmute yourself and ask your question.
Great. Thanks a lot, guys. Just given what's been covered already, it's a bit more of a holistic and longer-term one. It's clear there are some cancers where not enough ctDNA is being shared at an optimal point in time for Galleri detection. Do you think there's something you could do technologically to drive better early detection some point down the line in those cancers you are perhaps missing on these trials? Maybe just talk us through the direction of R&D from this point onwards. Thanks a lot.
That's a terrific question. I think I can say a few things about that, then ask Harpal as well. I think obviously our R&D efforts are squarely focused on how do we continue to improve the performance of Galleri on many dimensions. One thing that's very careful that we have to navigate is that what we don't want to do is get into the area of over-diagnosis, where we're finding cancers that are shedding very little bits of DNA and we're diagnosing those. That is one of the biggest concerns right now about the safety of cancer screening, is that we are over-diagnosing indolent disease. We've published now twice from the CCGA study that those cancers with indolent disease that we do not detect have remarkable survival at every stage, much greater than would be predicted based on the SEER data.
That the cancers that we do find that are shedding measurable amounts of DNA are the ones that need treatment and that need to be acted upon. We know that. While we want to continue to improve our limits of detection, we want to continue to improve our sensitivity, and we have several programs designed to do that, we need to be very careful not to get into this area of over-diagnosis, because that is a real safety concern. Harpal?
Yeah. I'll be brief, I think I'll make two or three quick points. The first, just to reiterate what Josh has just said, which is we could just change our specificity, we could find a lot more cancer today. We would be doing that at the expense of having many, many more false positives. There's two balances to be struck. One is avoiding substantially more false positives, because we don't think that's a good thing either for individuals or for health systems. Two, avoiding over-diagnosis. That's the first point I'd make. Second point I'd make is that, as Josh has just touched on, we do nevertheless have a number of research programs underway where we will be looking at improving sensitivity in those cancers we do want to detect.
It is interesting, when we look at the detail, that most of the ones we're missing are ones where we do have current screening programs or where they are already being found at stage 1. The opportunity to find them any earlier than stage 1 doesn't actually exist. Those are most of the ones we're missing. That's not to say we catch everything else. We don't. We do have a number of programs addressed at that. The third point I want to make is just an important one that we don't spend much time talking about, which is that actually the effectiveness of a screening test is as much about what happens after the screening test. If the diagnostic workup isn't done properly, the cancer might be missed. It's still there.
The test might have found it, but if the diagnostic workup isn't done properly, that is a missed opportunity to find that cancer. We know that that happens, not just in the NHS, but in the U.S. as well. One of the things I think is going to be really important going forward is the effectiveness of the subsequent workup that providers undertake when they have a positive test. What we've seen over time is that as physicians, as providers get more comfortable with the Galleri test, they realize just how strong the PPV is, and therefore the importance of properly working up a positive test when they find one.
It's a hugely important point. I'll amplify it with two facts. Both in the SYMPLIFY trial in symptomatic individuals and what we saw in NHS-Galleri, cancers that were deemed false positives in the first year were subsequently found in the next year or two in both of these trials at the predicted site by our test. That signals that either one of two things happened. Either the cancer was present and missed by the workup, either imaging missed it, endoscopy missed it, or it was too early to find by our conventional tests. I think Harpal's point is critically important, and that will improve over time as well. Okay. Well, with that, I really want to thank everybody for their participation. I want to thank our experts. Andy, I want to thank you, and Harpal, and thank you very much to our panelists.
We really appreciate hearing from you and how these data impact your practice and your thoughts about it. The goal of all of this multi-cancer early detection is to find more cancers earlier when they're more treatable and potentially curable, so that patients have the chance to live longer and more productive lives. Again, the NHS-Galleri trial provides this wealth of data that we will be studying for years to come. Really the opportunity to reduce the burden of metastatic disease. PATHFINDER 2 accentuates those data and further confirms the performance. We really appreciate all the questions, and thank you for your attention. With that, we'll close the evening. Thank you so much.
There are no further questions at this time. Thank you for joining. You may now disconnect.