GRAIL, Inc. ($GRAL)

Good day, everyone. Welcome to the GRAIL ASCO 2026 Analyst Call. [Operator Instructions] 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 2 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 3 leading physicians in the MSA space. [ Dr. Melinda Lasar, Dr. Nima NalboVizada; and Dr. Eric Su. ] 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. Now the goal of cancer screening is really to find cancer in individuals before the cancers have spray 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. Now 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 United States, we find about 14% of cancers with our current screening programs and 70% to 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 words urgency, action and groundbreaking technology that can make a difference and they can be implemented safely. The results of our randomized controlled NHS gallery trial of 140,000 individuals were presented Saturday morning by Dr. Charles Swan and the results of our 35,000 patient PATHFINDER 2 study were presented this morning by [ Dr. Karthik Girdhar. ] The results of these studies demonstrate the many clinically meaningful benefits that gallery has to offer for population health. We now know that across these studies, Gallery 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 Gallery study is the first time any MSET has demonstrated the ability to generate a stage shift and 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 adds substantially to our clinical utility evidence base. In fact, the NHS Gallery randomized controlled trial in that study, gallery found more early-stage cancers than all screen detected cancer spanned in the National Health Services screening program in the control group. Groundbreaking indeed. In addition, performance metrics such as PPD 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 MSE being added to standard of care screening, that we have the opportunity to actually eradicate the score and human toll of metastatic diagnoses in our lifetimes. And 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. And 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 2 large studies this weekend. The NHS Gallery trial, the first and only randomized controlled study of an MSA test was designed to demonstrate population level impact through the reduction of late-stage cancer diagnosis and increased cancer detection with an England National Health Service. The trial evaluated annual screening with the gallery test in addition to standard of care screening over 3 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 MSA interventional study in North America in an intended use population with no clinical sufficient of cancer. This study evaluated performance of single MSET test in a population of approximately 35,000 individuals and. And these studies add further to the broad evidence we've generated for Gallerie. Yesterday morning, the results of The NHS Gallery trial were presented by Dr. Charlie Swanton. And interest gallery is the largest first and indeed only randomized controlled clinical utility trial of an MSET 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 3 years and no clinical suspicion of cancer gave a blood sample and will then randomized one-to-one into the intervention or control arm at their initial study visit. The MSE test was performed on samples from intervention arm participants and those with a positive MSET 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 blood attention. Cancer outcomes were passively collected using national registry data sets for all participants. Participants were invited to return for 2 more annual blood samples and both arms had high retention rates across the 3 screening rounds. The 2 arms were very well balanced and generally reflective of the U.K. demographics of the target age group. The trial enrolled from laterite groups and those with lower education status which is typically underrepresented in research. Follow-up for the first 2 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 section, this screening trial was designed to rigorously assess the benefit of MSET 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 3 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 diagnosis between the intervention and control arms account for different links of follow-up times. This was done in a prespecified set of 12 cancer types responsible for 2/3 of cancer deaths in the U.S. and U.K. and in all routinely stage cancers, including and excluding prostate cancer. The primary endpoint of a reduction in Stage III and IV cancers was not met. And we'll talk about what we see here -- what we saw here in just a minute. As we use Stage 3 and 4 reduction will not be the only relevant measure of clinical utility, the study included several prespecified secondary end points such as the reduction in Stage IV cancer, increased Stage I and II diagnoses and MSET test performance. We saw a clinically significant reduction in Stage I cancers of more than 20% in the incident rounds, an increase of 16% in Stage I and II cancers detected and strong performance and safety metrics for Gallery. 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 detective cancers and a substantial decrease in cancers detected through emergency presentation. The totality of this data provides very strong evidence that adding gallery to standard of care screening can identify more cancers through screening and enables a state 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 then expect to see a reduction in late-stage cancers as the effect of the screening intervention becomes apparent. And this is exactly what we saw. When we look in the further detail of the data by screening round, we can see that there was a very large increase in cancer detected in the first or prevalent screening round. And as I'll show you in a minute, these are predominantly Stage III cancers. Overall, there was a 19% increase in Stage III and IV cancers during that prevalent round. There was a trend towards fewer Stage III and IV 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 III and IV cancers observed in the permanent 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 the 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 III cancers, particularly in the prevalent screening round. We believe the Stage 3 increase was driven in part by a number of Stage IV cancers being shifted to earlier stages, including at Stage III 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. And we would expect more of these cancers, what do we 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 III cancer is already prevalent in the population before any screening commences. Finding these cancers earlier means we can start treating those patients with the agency needing and in many cases, with the opportunity of curative intent. If we break down the 14% reduction in Stage IV diagnosis by screening rounds, we see that the reduction in Stage 4 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 to develop or progress between screening rounds and become detectable. Thus, as I mentioned earlier, the incident rounds most closely approximate the likely steady state impact of an annual screening program. Overall, in this prespecified secondary endpoint, a 14% reduction in Stage I 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 prespecified 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 123 specified deadly cancers evaluated, a diagnosis at Stage III improved survival rates dramatically compared to a diagnosis of Stage IV. You can see here that 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, 5-year survival is 64% at Stage III compared with around 11% at Stage IV. And not shown on this chart in prostate cancer, we saw a 25% reduction in stage IV diagnoses, where 5-year survival is 97% at Stage 3 but only 53% at Stage IV. Along with the decrease in Stage I cancer incidents, we also observed a 16% increase in stage I and II cancers for the 12 prespecified cancer types after 3 screening rounds in the intervention versus the control arm. And as you can see, overall, there were about 90 more cancers diagnosed at Stage I or II. A large part of this increase was in colorectal cancer with the rest split between upper GI, ovary and hemo 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 results and 1,937 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 prespecified cancers. Cancer signal detection accuracy was greater than 90%. The safety profile is also strong, focusing first on force positives across 3 screening rounds in the 70,000 participant intervention arm, there were 864 false positives. This means there was a positive gallery test but the subsequent workup in the system did not find the cancer. Now 303 of these false positive tests were in the first screening round on which we have 2 years of follow-up. In 54 of these cases, the participant was ultimately diagnosed with the 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 NSAIDs, it's the cancer detection yields that best reflects the overall sensitivity of the MSAT in totality as opposed to cancer-by-cancer sensitivities. The Gallery MCED has the unique feature of a single specificity that we optimize for unlike single cancer screening tests that optimize sensitivity. So in terms of overall cancer detection yield, the addition of MCED screening to existing NHS screening programs led to an approximate fourfold increase in screen detected cancers. Many of these cancers were detected in Stage I or Stage II. In fact, more Stage I and II cancers were detected by gallery 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 they needed to be detected through clinical presentation. And further, the addition of MCED screening decreased the number of cancers detected through emergency presentations by more than 25%. And as you may know, cancers detected in the emergency room represents some of the poorest outcomes and most costly cases. Of the 937 cancers detected by gallery, roughly 70% were in stages I to III and roughly 40% in stages I to II and roughly 20% at Stage I. 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. And in fact, most lung cancer cases are individuals who are not actually eligible for lung cancer screening. Now the ends get smaller to less prevalent cancers but you can see the breakdown of cancers by stage here. And 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 2 on the data that was presented this morning on our [indiscernible] 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 partisan study. In this study, participants with the positive results 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 MSA test in an intended use population. Participant population was representative across age raise 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%, an and CSO detection accuracy was greater than 90%. And the high CSO accuracy facilitated efficient targeted evaluation. Episode sensitivity caters diagnosed in the 12 months following the MCED test was robust, especially in prespecified clinically relevant cancer subgroups where we saw sensitivity of up to 70%. More than half of the new cancers detected by Gallery was Stage 1 or 2 and more than 70% of these have no USPSTF AOB recommended screening. Approximately 70% of the new cancers detected by gallery were detected at stages 1 to 3 when treatment with curative intent is more often possible. Overall, 6.5x as many cancers were detected through screening when MCED was used in addition to USPSTF grade A and B screening recommendations and 3x as many when used in addition to B and C screening recommendations. Gallery demonstrated a favorable safety profile, screening with a gallery test at a very low force positive rate and a low rate of invasive procedures. 85% of diagnostic procedures were noninvasive. There were 5 study-related adverse events reported during diagnostic evaluation and only in those with cancer diagnosis. Anxiety temporarily increased our participants with a positive 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, 5 study related AEs were reported during diagnostic evaluation. And as I said, only occurred in those with the cancer diagnosis and none are serious. In these data sets this weekend, we saw clear evidence of strong performance for Gallery. Across the 2 studies, which included almost 180,000 participants together, we see consistent evidence that gallery is able to detect cancers that standard of care is not finding today. This is the first demonstration of clinical utility via stage shift for an MCED test. In a randomized study, we demonstrated a greater than 20% reduction in Stage IV cancers a double-digit increase in Stage I and II cancers and a 25% reduction in cancers diagnosed after emergency presentation. In the 2 studies presented this weekend, we saw that adding Galleri to standard of care, increase the number of cancers detected by screening by between 4x nd 6.5x. Today, the standard of care finds only about 6% of counters in the U.K. and around 14% of counters in the U.S. Adding galleries 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 gallery. Multiple studies have now demonstrated a very low false positive rate and a high PPV in intended use populations. And the high accuracy of galleries cancer signal origin results enable efficient patient-centered care. The Gallery 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 gallery test is the only MCED test clinically proven through a randomized controlled trial to increase early 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 Gallery. 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 diagnosis, 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 3 physicians, [indiscernible] I'm going to invite each of them to briefly introduce themselves and describe their medical practice.

Thank you. Good evening. I am [ Dr. Malaga Masa, ] and I'm an associate professor at the University of Pittsburgh and Family Medicine position at UPMC and I run a primary care precision medicine clinic where I have introduced [indiscernible] detection screening since it was released out to the market. And I would like to pass it off to my colleague.

Thank you. Thanks, Melinda. [indiscernible] I'm a radiation oncologist at the Oregon Health and Science University in Portland, Oregon, and I also lead our early detection and 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 1, 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 nonsurgical curative treatment options available for patients with early-stage cancers. So certainly, early detection is near and dear to what I do and the patients that I see.

I'm Eric So, I'm an internal medicine physician in private practice in Los Angeles. I have now done 1,277 gallery screens in 3.5 years and have had 6 true positive gallery tests. I think it's incredible stuff. I think it's only going to get better.

So maybe Eric will start with you. You're actually presenting actually on Monday, your experience with the gallery test in your practice here at ASCO. How long have you been offering gallery to your patients? And who do you recommend it for?

Sorry, I only learned of gallery cancer screening in September 2022. I only learned a bit because one of my patients asked me about it. I've never heard of it before. We reset 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. But here I am 1,277 screenings later with 62 positives, I do think we're there. And it's something that I like to talk to essentially all of my patients about it 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 gallery cancer screening, but maybe perhaps they would want their parents to consider something like this. So it's really a daily conversation that something like this is available, a blood test in constrained for over 50 different kinds of cancer. It's being described as a liquid biopsy as a capsid in time or if it's negative, you've got a 99% certainty of having any of those 50 different costs of cancer at that moment in time, which can be some piece of mind. It is technically recommended for anyone over the age of 50 because that's when everyone's risk of cancer increases. But particularly if you have an own fame gave some kinds of cancer and you consider doing it on an annual basis not as a replacement for any current cancer screening guidelines like. And you will memory-making at age 40 or periodic not starting at 45, but it's meant to be as an adjunct to try to give ourselves the best chance to identifying any 1 of these cancers most of which we don't have any way to screen for. And if the overall risk of false positive is 0.5%, which is unheard from the cancer-screening world. If you did get a positive dollar test, we now see the positive predictive value and actually meaning of cancer is 60%. So I tell patients that a positive pastime you have cancer but it certainly raises the question and that a positive test tells you what kind of cancer with now 91% accuracy, and it tells you what 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 Gallagher screening 1 to 2 months later, which then the company pays for. If it's positive again, and you look for cancer again and perhaps identify something, and that first has to appears to have been a true pause. May have been at a preclinical stage with the conventional studies we have available to detect cancer couldn't find anything or sort on follow 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 in talk to Eric is poster on Monday. Melinda, how have you been incorporating Gallery into your practice? And how did you first hear about it and decide to incorporate gallery?

Yes. So I first heard about it actually when our executive health wanted to implement this testing for their patients. And 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. So 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 a to over 50, but by so we were positive for hereditary cancer risk variants, those who have had significant family history, but may not have a genetic risk that on sound and other individuals with exposures or chronic illnesses that make them at higher risk for cancer. And so this has been a great adjunct that we have been able to educate our patients about -- we normally tell them about the opportunity if there are new patients, and we're picking 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. And then 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.

Nila, as a principal investigator in the PATHFINDER study, you followed a large number of patients on gallery. What have you learned through this process? And any specific patient examples come to mind?

Yes, absolutely. So yes, like I mentioned, we've been rolling on Pathfinder, Pathfinder 2 in [indiscernible] study and have nearly worked up 100 patients with signal positive findings at OHSU and 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 of Cancer Research to speak on this topic and I was invited by the blood pack consortium to speak on this topic. And the message that I was trying to relate to the packed room was the strong value in the cancer signal origin result that comes from the signal positive finding. And I was leading to the investigators and the other test developers in the room to really work on this because my experience of working with the gallery test and seeing the CSO finding is that it's incredibly helpful. I'm a radiation oncologist I examined imaging all the time. I use it as part of my treatment plan and indeterminate findings are all over the place. And for a patient who has a signal positive finding who has a potential and what radiologists may call an indeterminate finding, but then that matches the cancer signal origin, especially with a positive predictive value 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 along with this indeterminant finding. And a good example here is a patient who had a signal positive for gastroesophageal cancer, and they had previously many years ago, had a gastric bypass surgery. And with the gastric bypass surgery, basically excludes the bottom portion of your stomach from your esophagus. So we provided the cancer signal origin specified WorkHub, which is an upper endoscopy and the endoscopes was only able to access the first 1/3 of the stomach or so. It was normal. And before deeming this patient a false positive, we obtain a whole body imaging whole body imaging with the pet CT revealed some subtle lividity in the bypass portion of stomach that was inaccessible with routine outpatient endoscopy. And I think in the absence of the cancer signal origin finding subtle avidity would have been kind of put aside going to extra distance to biopsy that area is a big deal. And I sat down my [indiscernible] looked at the imaging. I explained the cancer [indiscernible] and the PPV of the test. That portion of the stomach was able to be biopsy but had to be in the operating room under general anesthesia using this very long endoscope that goes into the small bow in back into the bypass portion of systemic and it was a biopsy-proven gastric cancer, early-stage gastric cancer. And without that cancer signal origin, we would have completely overlooked it, and this patient would have presented with Stage I cancer. Another example is a patient who had an anorectal signal and underlying signal positive work up and with that, you automatically go to endoscopy with the lower endoscopy and that patient came back positive for an early-stage anal cancer. And this is important because, certainly, this is a curative treatment option. And because it was found early stage in an asymptomatic nonsymptomatic situation, this patient is able to receive less radiation, less chemotherapy, much less side effects with fantastic survival. And interestingly, when the colorectal surgeon, they refer the patient to who called me back with the result of the biopsy, you relayed the result. But then the second question was, how can I get this test? He is totally shocked by the sensitive test to pick up in that early stage all 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 the FDA advisory panel on MCED was something that the FDA felt was an important component of any MCED. Eric, I want to want you to think about the current status quo of screening in relation to what we saw both in NHS Gallery, where we saw 4x 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 the physician and to your patients when you think about the current status quo?

Sure. I mean when you understand when you understand the status quo with 5 current cancer screening guidelines, we're only able to capture 29% of the cancers that people are dying from leading 71% of the cancer and people are dying from that we have no available cancer screening metrics for and 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 [indiscernible] enrolled 6,600 patients. They saw a twofold increase in the cancers detected when compared to standard of care. And now entering that with Pathfinder 2, there is a threefold increase in overall cancers detected when compared to standard of care. And that with NHS Gallery, 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 NZ testing when performed at scale. And we now have evidence showing that annual gallery cancer screening can reduce as 4 cancers by year by 22%. And by year 3, by 26%. And so by shifting cancers for away from metastatic presentation and closer to earlier-stage detection, we're creating so many more opportunities to intervene when curative treatment needs to be possible. And most importantly, where the opportunity to reduce cancer mortality is the greatest. And that's, I think, what's really stood out to me this weekend.

Melinda, what were your reflections after seeing the presentations this weekend. What did you find most compelling about [indiscernible] and PATHFINDER I study results?

Yes. It was really reflecting all weekend after listening to each of the presentations. And last night, I was really thinking that -- as a scientist, I have reviewed this data over the last 4 years as it continues to emerge and evolve. And I have really seen the established scientific validity of this screening. And 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. And I now have hope for a different future. and a future where we can actually screen and catch more than just 5 cancers with an opportunity for treatment with curative intent, which is transformative in my life span. As a patient, I am convinced that I am here today because my melanoma was diagnosed at Stage 1 in 2018. And I myself have added this to my screening regimen every single year to ensure that I have the best opportunity to keep that going. And as a family member, I got to see my own set mom diagnosed with Stage IV glioblastoma in the emergency room after I said an onset seizure while she was out for a walk after dinner 1 night with my brother. And he then brought out of college and took care of her until her passing and never return back to university. And so -- this -- 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 in their families from cancer.

Thanks so much for sharing those personal experiences. -- that's what we're all GRAIL employees to GRAIL. And that's what keeps us focused on the mission that we have. Lima, you've heard Eric and Melinda 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 -- it gives them a shot for curative treatment and -- that's where people are seeing me in my clinic for.

They understand that a lot of these cancers are really aggressive. And they're aware of that. They've been told that, all their research shows that. But what patients are looking for or some hope and a shot to cure this cancer. And that's really what happens in the Stage II situation. I see patients in my clinic from the stage 1 situation to stage 4 situation. And in the Stage IV 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. But in the radiation oncology world, we're typically brought in and involved to treat these Stage II 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 cancer. A great example of that being Stage III lung cancer. Furthermore, the treatment intensity and toxicity, as I mentioned with that annual cancer patient is far fewer and far less once you're able to bring the stage down from stage IV.

Eric, you talked a little bit about the positive predictive value of gallery. How does that compare to other screening tests that you currently use? And how do you describe the benefits of a higher PPV with gallery to your patients?

So when I was first introducing gallery to patients, I was working with Pathfinder 1 information. And at that time, the positive rate to value was 43.1%. And oftentimes, people will hear that and say, so if I do this test, I get a positive test. I have a less than 1 or 2 chance. It's actually having cancer. That's not great. But I really want to do this test and subject myself to that potential of going down that rated pole and not being found to have cancer. But then I mentioned, well, what's the positive predictive value of an abnormal mammogram and actually, you need someone who has breast cancer 4.4%. What's the positive predictive value of a positive [indiscernible] stool test, which is being used as potentially an alternative to colonoscopies and is fully covered by all insurance and Medicare and actually meaning someone has colon cancer, 3.7% -- so 43.1% positive predictive value of a positive gallery test meaning someone has cancer is in order of magnitude better than what we're doing as better of care. And now we're dealing with the totality of the PATHFINDER trial data that, that positive predictive value is 60%. And with NHS in the prevalent seeding round of the positive predictive value is 58%. So again, in order of magnitude, better than what we're doing as standard of care. Nothing like this around anywhere.

Thank you. And then 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 NS Gallery study, we observed a substantial reduction in ER diagnoses in the intervention arm with Gary. Can you describe what it means to a patient and their family to be diagnosed with cancer in the ER?

Yes. I still not only did I share the story of my stepmother, but I am a hospice Medical Director and have been for 17 years. And seeing patients diagnosed with a very advanced cancer and the ER is incredibly dramatic to both the patients and to their family. They often have very poor outcomes and very little time to make decisions. And 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, treat. And that is true if someone has an earlier stage detection. But when it comes to presenting that symptomatic in the emergency room, most of the time, it's incredibly late stage and diesel metastatic. And so they are not great options, and that's when I get called in to meet with those families. And I think it's devastating. So I think more than anything, what I've heard from patients over the years is hope is critical. And so not only does early detection prevent those types of traumatic events, but it allows us to find the detect cancer with intent to treat successfully, and that is what hope is all about, and that's really a gift.

Melinda, Nilha and Eric, thanks for sharing your perspectives and really bringing to life what Gallery means in your medical practices and what it means to your patients and brought to life what these NHS Gallery and Pathfinder 2 results mean when we actually implement the gallery tests within medical practices. I'm now going to open it up to questions on the line. So over to you, moderator, please.

[Operator Instructions] move to the question-and-answer session. If you have joined via webinar, please use the raise hand icon, which can be found at the bottom of your webinar application. [Operator Instructions] Our first question comes from Subu Nambi with Guggenheim.

Josh, I want to give you an opportunity to address the points brought by discussions yesterday regarding 2 points. One, catching less Stage 4 may not improve our co to detecting cancer in stage 1 and 2 that are already screened by standard of care and that casting rare cancers may not be cost-effective. What will be your discussing -- discussion points. Thanks,

Subu. This is Josh. Let me take the first -- the one. First about cost effectiveness. So again, most of what Gallery finds are cancers that are not detected by current screening. In fact, almost 3/4 of the cancers we find are cancers other than what is found by mammography or colonoscopy or low-dose CT or PSA testing. So that's really not an issue. As it relates to cost effectiveness, we've already demonstrated and published numerous cost effectiveness analyses that chose that given our current set of assumptions, gallery is a highly cost-effective intervention. Those are being rerun now with the latest data, and 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 were found through MSA screening. So it's curious to hear oncologists say things like we just don't know if it's a 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. And so 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 1 through 3 provide the opportunity for curative intent. Yes, I will just add 1 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. Stage IV colorectal cancer has a 5-year survival rate of 11%. And the Stage 3 colorectal cancer has a 5-year survival of 64%. I challenge anyone to say that's not meaningful. I just don't -- I fundamentally don't accept the premise that finding that cancer at Stage 3 rather than Stage 4 is not beneficial for the patient.

No, I hear you, but then when you sit our people argue that there are better sensitivity tests already out there. So why do we need this multi-center multi-cancer test altogether adding to the cost? Well, 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 PAR2 study showed was that we have the opportunity to find 60% of cancer through screening. So 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. But the complementarity is, I think, very strongly demonstrated when we can go from 14% of cancers detected through screening to 60% of cancer infected through screening.

And Subu, just last point is that while we're not suggesting colorectal cancer was used by HARP 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 to 15 years ago, who 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 forgo treatment. They're unlikely to find any patient who would agree with that.

I just want you to hear more thoughts on this. recognizing that reimbursement is predicated on FDA approval, do you come out of the 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 space 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 Gallery trial and all of Pathfinder 2. They're going to be focused on clinical validation and clinical performance. And 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 Purple, how compelling do you think these data are.

Our next question will come from Dan Brennan with TD Cowen.

Great. Maybe just following up on one Subu's question. There's a lot of discussion about where the benefit to gallery is, obviously, under-screen cancers screens out, although the data looks encouraging and certainly CRC and lung. But I'm just wondering from the NHS Gallery data, how would you rank order the unscreened cancers where you think galleries the biggest benefit? I know you've got slides selling Stage 1 and Stage 2 ship and Stage 4 shift as well by center type intranet. And then as a follow-up to that, if in fact, the FDA were not to approve gallery label with lung or CRC, how would that impact the value of gallery from a clinical utility and 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 to -- back to the doctors and their patients. We will continue to find interval colon cancer inter lung cancer interval breast cancer, you see that throughout our studies. So 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. And as we've stated, we found over 150 different types of unique cancers already through these Val studies. And I'll turn it over to Harp 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. Because actually, the reality is we're looking at so many different types of cancer, which have very different levels of aggressiveness of prognosis of incidents in the population. And so 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. And so colorectal screening in the U.S., fantastically effective though it is find 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. So there is huge complementarity here. And even in breast cancer, we're finding interval cancers between screening rounds the mammography program misses. So I just -- I hesitate with the notion of rank ordering. I think there's benefit really across the board here.

Yes, if I can add 1 comment. This is Nima. In the state of Oregon, only 10% and we've looked at this at the Oregon Health and Sincerity, only 10% of people that are at high risk and eligible for a low-dose CT screening are actually getting it within the state. And there's a multitude of factors there in regards to access, a stigma, Oregon's a very rural state to be close to a CT scanner to get these exams. And furthermore, even for more common screening practices like mammograms, I mean, very recently, we had a signal positive breast cancer in a patient who skipped out on early mammograms because they were worried about the radiation exposure from the mammogram. And the gallery test here identified the early-stage breast cancer in this patient. So 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 is getting them.

Great. And then maybe just on the data, just as a follow-up, the 2 part. You mentioned that you think there's going to be a lot of late-stage cancers that are going to show up in the control arm just given the dynamics what you saw. So I'm just wondering kind of how we might see that come out over what time frame? Like when will that get reported? Will it get reported? And then b, the study was run at 3 years. And feedback from experts reflected like a screening study like this probably needed to be run a lot longer in order to catch the full extent of it. So the performance of the asset was improving year 2 is improving at year 3. Is there any way to think about like at what point it would ask them to. I don't know if that will be something you guys can do. Obviously, the study stopped, right? So this -- it would be all modeled out. But I'm just wondering kind of the trajectory that you saw at year 3, kind of what would that imply like would be playing out further?

Yes. So let me -- so on your first question, which is a further follow-up, I think we've said a couple of times now that we want to continue to follow up the NHS gallery population for at least another 12 months. We are hopefully close to getting that agreed with the NHS. Assuming we do, then that data should be available analyzed by I would hope, Q1, Q2 next year. And in terms of where and when we will present it, that's still to be determined. But that's roughly speaking, the time line that we would expect to have that information on. Your second question, which is we did all this very quickly. Yes, we did. And 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 prespecify 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. And actually, the more important point is that -- we wanted to get to results quickly because thousands of people are dying from cancer every day. And I 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.

[Operator Instructions] Your next question comes from Kyle Mikson of Canaccord.

Question trial does seem watch that there would have been about as cancers that have it in the problem ground with ibet Stage 3 was funded by far. If you foresaw or expected this, I think Harpal mentioned that, did you try to deprioritize or remove the promo from the primary end point during those initial trial design discussions. I know it's like a tough question just for context would be interesting. And then secondly, given this round was the most problematic, but it's the only an trial that we provided to the FDA. Can you try to provide supplemental data from is around to the FDA. They've opened on safety performance, but they like to kind of have to look a little bit at quickly utility possible for this.

Yes, interesting question. I mean, the challenge with it is once you prespecify a primary endpoint, it's really not appropriate to change it when you see the data. And so I understand the question. I understand where it comes from, but it just wouldn't scientifically have been the right thing to do, and we would have 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 but 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 found the important we're seeing the substantial Stage 4 reductions in the incident training rounds.

And Kyle, maybe I'll add one thing. You heard Dr. Swanton say yesterday, that this study was designed almost 8 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. And that -- those estimates were off -- and there was just quite a lot more Stage II cancer than was ever anticipated. And had that been anticipated, perhaps the study would have been designed to be to have longer new screening rounds or things like that, but nobody knew that. And so to Harp's point, it would not have been appropriate to have changed anything based on what we had prespecified and I think doctors want and made that point quite clearly yesterday.

I think it is -- sorry, just to add one quick comment. It is just worth reiterating. One of the things that we've 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 -- and it will give us huge insights into how we think about both the prevalence of cancer but also what we might do about it going forward. And

Kyle, Harpal's point is whatever the primary endpoint was doesn't dictate what you actually observed in the trial. And to Harp'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.

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 3 years wasn't long enough. And so when I explain that to my patients, then I might say, we need to do annual screening for 4 years to actually feel confident as opposed to 3 years, which is not a reflection on the technology or a reflection on the ability to capture cases earlier, but really a reflection on how we will eventually see population shift. And that is -- can you still a pretty valuable information that we've won from the science. And even more excitingly, I get to counter that with even in that time frame, we may catch 4x more cancer and catch cancers that we've never been able to screen for before.

Our next question will come from Catherine Schulte, Baird.

If I just think about NHS gallery, you showed reduction in Stage 4 reduction in combined Stage 3 and 4 by the third round of screening. An increase in early-stage diagnosis and increase in overall cancers detected. And yes, 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. But do you have any plans to evaluate that and maybe absent mortality data, just -- what do you think is the metric that should be viewed as the best measure of success for net tests, given what you know today?

Well, it's a very soft 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 him said. So I think while people like to talk about that, 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 Harper has already talked about the mortality differences between these different stages that we see at the population level. So I think that study is not going to get done. It's really important to remember that we have agreed to explore mortality in NHS gallery, but NHS gallery 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. But your bigger question is what is the right endpoint. I don't think there is a single right end point. 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 dread full cancers when they're already metastasized in our lifetime. And these data that Harpal has just presented to you are the best data available to give the hope that, that is actually going to happen. So 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?

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. We want to be able to do something about these cancers. And 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 is meaningful for health systems and it's what's important to populations. So finding cancers before we run out of treatment options or even better, finding cancers at a stage where 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 Gallery. Some of that will simply be passive follow-up of the individuals, where we'll compare the number of people who had died in the 2 arms at time points into the future. As Josh importantly pointed out, that's not powered, but we will look at it and we reported -- 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 some time in the 2028 time frame and we'll report on that when we have it.

Melinda again, I just wanted to I also just to this from the primary care perspective, the utility also has to be about feasibility of acceptability, right? So if we continue to think that we need to expand cancer screening and include cancers beyond our current 5 that we're able to screen for it's not feasible to do that on a single organ basis. As a primary care provider, you would spend all of your time then trying to check down and get patients to achieve their cancer screening. And it wouldn't be acceptable to the patients either also would have a dramatic increase in the rate of salt positives, which would lead to also some significant consequences. And so 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 and as all of you have heard us say before, those false positive rates accumulate in individuals. So a 50-year-old female who's getting a mammography cone cancer screening test cervical screening test and let's say they're a smoker and they get low-dose T1s, 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. Now imagine a world with 5 more single cancer screening tests. It is untenable not feasible and there would be major safety concerns associated with that. So in our view, there is no alternative to really screening for multiple cancers beyond the 5 that we have now without an test.

Our next question will come from Puneet Souda with Leerink Partners.

Congrats on completing presenting the largest trial in early detection. This is a multipart question. It's rather simple. The first part is really simple. Look, but 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 in the U.S. like was on February 19, when the headline for primary endpoint not meeting came about versus the detailed data cuts that you're providing today? Would this additional data details change that prescription beaver versus February -- and do you think you have to ask FDA on changing the marketing materials since you're already engaged with them? And 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 read this trial again?

Thanks for your question. So I'll take the first one. So as I outlined on our last earnings call, we are certainly hearing from physicians, 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 by the our medical teams and our sales teams on the detailed data that we presented here at ASCO on Paint and NHS Gallery because going forward, we're going to be able to answer those questions. And as you've seen, the data are simply remarkable and we believe they're going to be transformative. So I think they're going to have a positive impact on prescribing going forward. But I really shouldn't be the 1 speculating on that. We have 3 physicians on our panel now. So 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. So I got plenty of e-mails and phone calls following the headlines 3 months ago, cancer screening fails, major trial. And I thought they were really unfortunate headlines because I think what they threaten to do is lender the entirety of this massive landmark never before tried trial that's completely meaningless to wonder everything else GRAIL has done in the last 5 years, that's completely meaningless. And where I tell patients and colleagues -- is that what the NHS trial has shown and I can tell them even more based on this weekend. Greater than 20% reduction in Phase 4 diagnosis by years 2 and years 3, I saw a fourfold increase in overall cancer detection rate when compared to standard of care and a substantial increase in stage 1 and 2 cancers 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. And I would say that for physicians who are already ordering gallery, I 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 consumers alike when the other competitors, I don't think have any real-world interventional prospective trust that prove what they are showing in the case control trial data actually works in the real world intended patient use population. And that's everything that GRAIL has done in the last 5 years. So I remain hugely optimistic about the potential of multi-cancer early detection ingraining the premarket approval advocation on the FDA on January 29, soon thereafter being the President signing into law of Medicare and multi-cancer Elite detection screening coverage Act, establishing a pathway for Medicare reimbursement if [indiscernible] intestine becomes FDA approved. So we're heading in a direction where this maybe come back as a valuable tool. When we understand again that the status quo is far from perfect and potentially covered by Medicare, after which product insurance companies might follow along as they ordinarily do. And this may become much more widely available to everyone that we believe deserve access to something like this. I guess all that, I mean, 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 seats from the primary endpoint in my practice work with the technology, I know it's been working. I know it picked up early-stage cancers that patients would have otherwise known about and the richness and the granularity of the data in regards to the incidents and prevalence rounds of the screening are quite remarkable and just so excited to see another year or 2 or a follow-up and that's because really, the data is actually incredibly encouraging. And I think the challenge for Grill is how to disseminate this information to the lay press in a late way and who could do that with because trial failed is probably more click base than a trial failed, but there's actually some really encouraging signals that we need to wait for and look at that I think is more challenging.

So yes. 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 and the opportunity to touch 4x as many cancers as we've been taking with standard of care thus far. And then 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 improve gallery, which we obviously hope it will, we will have to relook at what the label is and what our marketing materials are, but we wouldn't do anything like that until at that time. And then Harpal, I'll ask you the final question he asked about what have we learned? And is there anything we would have 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 definitely learned some things. We've learned that -- as I touched on earlier, there's a huge amount of undiagnosed relatively late-stage cater in the population. That's quite a sobering insight actually that we've discovered from this trial. And 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 have done the design in a different way that it wouldn't be appropriate to do that with the benefit of hindsight. But I would -- what I would say is a trial has to be designed in the context of what you know today. And what we know today is that the treatment landscape is very different now from what it was 10 years ago. We can treat many, many Stage I cancers now, which wasn't possible 10 years ago. And the fact that we can do that means that actually finding cancers before they reach age is a really fantastic opportunity for transforming cancer outcomes. And 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 IV disease and finding cancer before it's metastasized. So hopefully, that answers all your questions.

Our next question will come from [ Colin Titcmark ] from Morgan Stanley.

Just given what's been covered already, it's a bit more holistic and longer-term one, it's clear that there are some cancers where not enough ctDNA is being shared at an optimal point in time for gallery detection. But do you think there's something you could do technologically to drive better early detection, some point down the line in those cancers you're perhaps missing on these trials. And maybe just talk us through the direction of R&D from this point onwards.

That's a terrific question. I think I can say a few thoughts on things about that, and 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 Gallery 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 overdiagnosis where we're finding cancers that are shedding very little bits of 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. And 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 and 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. And so we know that. So 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 overdiagnosis because that is a real safety concern. Harpal?

Yes. I'll be brief, but I think I'll make a few quick points. The first, just to reiterate what Josh has just said, which is -- we could just change our specificity, and we could find a lot more cancer today, but we would be doing that at the expense of having many, many more force positives and so there's 2 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 and two, avoiding other diagnosis. So that's the first point I'd make. Second point I'd make is that, as Josh 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. And 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. And so the opportunity to find the many earlier than Stage 1 doesn't actually exist. And so those are most of the ones we're missing, but that's not to say we catch everything else. We don't. And so we -- 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 capital might be missed right? But 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. And we know that, that happens not just in the NHS, but in the U.S. as well. And so 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. And what we've seen over time is that as physicians, as providers get more comfortable with the gallery 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 2 facts both in the simplified trial in symptomatic individuals and what we saw in NHS Gallery, cancers that were deemed false positives in the first year were subsequently found in the next year or 2 in both of these trials at the predicted site by our test. And that signals that either 1 of 2 things happen. Either the cancer was present and missed by the workup, either imaging missed endoscopy missed or it was too early to find by our conventional tests. And so 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 for our panelists. We really appreciate hearing from you and how these data impact your practice and your thoughts about it. Again, the goal of all of this multi-cancer lead detection is to find more cancers earlier when they're more treatable and potentially curable so that patients have the chance of longer and more productive lives. So again, the NHS Gallery trial provides this wealth of data that we will be studying for years to come and really the opportunity to reduce the burden of metastatic disease. Pathfinder 2 accentuates those data and further confirms the performance. And we really appreciate all the questions, and thank you for your attention. And 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.