PATHFINDER-2 Key Takeaways
Design
Prospective, single-arm registrational study of GRAIL’s MCED blood test — run in-trial as the investigational MCED-V2 device — added to standard-of-care screening. 35,883 adults aged ≥50 with no clinical suspicion of cancer enrolled at 32 US and Canadian sites (ClinicalTrials.gov NCT05155605); 35,878 in the primary analysis population, 32,007 analyzable for MCED performance with 12-month follow-up, 35,335 analyzable for safety (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis). No comparator arm — the study measures test performance and safety, not survival or mortality outcomes.
The Device: MCED-V2 In-Trial, Galleri Bridged
The commercial Galleri test is — per the FDA — “a different device from MCED-V2,” with differences in assay workflow, classifier, and bioinformatics pipeline. Galleri’s FDA-package effectiveness figures were obtained by bridging: Galleri was re-run on frozen plasma from a weighted subset of trial participants (12-month sensitivity 35.0%, specificity 99.85%, PPV 77.0%; 303 cancers, weighted N = 21,418, data cutoff Dec 31, 2024). The FDA presents safety results from MCED-V2 and considers that primary safety analysis an approximate estimate of Galleri’s safety profile (FDA Executive Summary, Sept 2026). Never mix the as-run MCED-V2 figures with the bridged Galleri figures.
Test Performance (MCED-V2, as run in-trial)
Positive predictive value 60.3% — of 287 participants with a cancer signal detected, 173 were diagnosed with cancer. Specificity 99.6% (false-positive rate <0.4%); cancer signal origin prediction accuracy 91.3%; episode sensitivity 39.3% across all cancers and 69.8% for 12 prespecified deadly cancer types (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; GRAIL Press Release, May 31, 2026; MCED-V2 data).
Cancer Detection
440 participants were diagnosed with cancer during 12 months of follow-up; 264 (60%) were screen-detected (MCED- or guideline-screening-detected). Adding the MCED-V2 test to USPSTF A/B recommended screening increased the number of screen-detected cancers roughly 6.5-fold, and roughly 3-fold when added to USPSTF A/B/C screening including prostate — descriptive, single-arm comparisons, not a randomized result (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; MCED-V2 data).
Safety (MCED-V2 primary safety analysis)
Per the FDA’s screen-positive framing: of 218 participants who underwent diagnostic evaluation for a positive MCED-V2 result, 159 (72.9%) had at least one invasive procedure; among the 90 with no cancer diagnosed within 12 months (false positives), 43 (47.8%) had an invasive procedure, including 4 surgical procedures and 33 endoscopies (FDA Executive Summary; MCED-V2, DCO Dec 31, 2024). False positives waited longer for diagnostic resolution (median 75 vs 36 days for true positives; FDA Executive Summary). At the population level, 0.6% of the 35,335 safety-analyzable participants had an invasive procedure (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis — secondary, all-participant framing). No serious study-related adverse events were reported during the diagnostic workup as of data lock; one serious adverse event related to diagnostic workup was identified after data lock, follow-up ongoing (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis).
Regulatory
The Galleri test is not FDA approved or cleared; it is available in the US as a prescription-only laboratory-developed test. GRAIL submitted a PMA to the FDA on January 29, 2026 under Breakthrough Device Designation, supported by PATHFINDER-2 and NHS-Galleri data. The FDA’s Molecular and Clinical Genetics Panel advisory committee is scheduled to review the application September 23, 2026 — the first FDA advisory committee review of an MCED test PMA (FDA.gov, Advisory Committee Calendar; GRAIL PR).
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Top KOLs Discussing PATHFINDER-2
Centerpiece — @brianwalcottmd’s read of the MCED data and its framing:
Imagine a blood test that catches 50 cancers early, before any symptom. That’s the GRAIL Galleri pitch, and the biggest trial ever just reported it at ASCO 2026: NHS-Galleri, a randomized controlled trial of 142,250 people in England (Swanton et al., ASCO 2026 Abstract, NCT05611632 / ISRCTN91431511). Here’s what the headlines skipped. The trial’s pre-specified primary endpoint was reducing cancers caught at a late stage, stage III and IV combined. It missed. No meaningful difference versus the unscreened group. So the press release led instead with a secondary finding, the stage IV number. This is not a Theranos situation. The test is real and the engineering is genuinely impressive. But the data is being framed to look miraculous.
— BrianWalcottMD (@brianwalcottmd) Jun 23, 2026
The other sleight of hand is the false-positive number. GRAIL leads with “specificity 99.6%, under 0.4% false positives,” which sounds flawless. But when you screen mostly healthy people, where cancer is rare, the number that matters is positive predictive value: when the test says “cancer signal detected,” how often is it right? About 60% in PATHFINDER 2 and 52% in NHS-Galleri. In plain terms, roughly 4 of every 10 people who get a positive result go through a full cancer workup, scans, biopsies, weeks of fear, and are ultimately told it was a false alarm. The test also misses most cancer overall, catching about a third, and it’s strongest at finding disease that has already advanced, the opposite of what screening is for.
And the question that decides everything is still open: does finding cancer this way help anyone live longer? Stage shift is a surrogate, and the cancer-specific mortality data from this trial are still being collected, years away. Catching something earlier is not the same as living longer.
Maybe some utility in monitoring response to treatment or recurrence? 🤷
The test is available commercially in the US for about 1000$ (annual). Would you get one? Have you had one?
Sources: NHS-Galleri primary results, ASCO 2026 (Swanton et al., NCT05611632). This is conference data, not peer reviewed yet.
PATHFINDER-2 Top Tweets
𝕏Besides, neither are really published yet.
We just have some charts from presentations at major meetings
I will just make a few points and leave it at that
The NHS-Galleri is a great study that is also a major missed opportunity
Props to performing a RANDOMIZED study of 140,000 people !!! 70k in each arm
But the primary endpoint studied was “reduction in diagnosis of stage 3/4 disease.
This was an ambitious but reasonable endpoint. Those are hard to cure diseases.
But the missed opportunity was that they should have done an overall mortality endpoint.
This was the NHS and they could’ve followed these folks for a decade or longer to get a read on whether serologic screening really made a difference at the population level
They did not go there. Probably did not want to
The fans were disappointed that the study missed its primary endpoint - no net reduction in stage III/IV disease
So they pivoted to the secondary endpoint, reduction is stage IV disease. This is not inconsequential since most stage IV cancers are INcurable, while stage IIIs are potentially curable, albeit at low rates.
They showed a modest reduction in stage IV disease downstages to stage III - about 25% reduction. This is fair, but for 70,000 people tested, that means about 100 theoretical patients were downstaged. And since a lot of stage threes are still not cured, like, lets say 50-75% are NOT cured, that means we only saved 25-50 patients.
Wonderful if that was you, but we had to screen 70,000 people to save 25 - NNT about 2500. I am not sure that is much to brag about, especially when you work in cost.
In the US, they did Pathfinder2, which is NOT a randomized study, so we can’t really learn anything in a comparative sense. Also, it is only the 1st year of a 3-year study.
This is important and a credit to them, because the first year you do a screening test you are assessing “prevalence’ - that is the whole population level of a disease (as detected by the modality). It tends to be higher.
Once you complete the prevalence round, you are only picking up “new” cancers and this is a more rational metric. Once a screening program is up and running, it is the incidence of NEW cancers per interval (typically a year) that matters most.
But since the “total number of cancers” is higher than “the number of new per year” the value of a screening program declines after year one. So kudos to them for checking this.
But we are in year one with 2 years to go.
Unfortunately, beyond a rough estimate of sensitivity and specificity of the test, we will not learn much about the impact on the population at large from mass screening
And lastly, without real long term follow-up, it will be hard to tell the impact of “over diagnosis”
This is the odds of finding a clinically irrelevant cancer.
One that is really cancer, but was never going to harm the patient.
Like the Korean thyroid cancer study. All those thyroids removed, and no extra lives saved
Without long term follow up, we can’t know if the test truly “migrates” stage 3s and 4s down to 1s and 2s … or if we are just finding 1’s (mostly) and some 2’s that are not clinically important
What were the bottom lines
Slightly different results from NHS-Galleri (UK) vs Pathfinder2 (North America)
NHS-Galleri (all three rounds)
True positive - 937
False negative (misses) 2114
False positive - 864
True negative 193,231
Positive predictive value about 50%
Half learned of a cancer diagnosis thanks to the test
Half were misinformed and went off on a work-up that was solely caused by the test
And 2114 received a false negative.
That’s a lot - that means that you can’t stop regular screening.
On the US side, slightly different
True positive 173
False negative (misses) 267
False positive - 114
True negative - 31,453
Positive predictive value about 60%.
Better than the UK, but remember this is year one.
The numbers will change after years 2-3
I don’t feel like crunching the numbers for a cost-benefit analysis but this is how you need to look at it
Costs
Raw cost of the tests at a population level
Add costs of working up positives
Tally the number of people harmed by diagnostic intervention
Benefits -
Again, we really can’t get benefits without a proper long term comparison arm
But the benefits ought to be lives saved from the test and advanced cancer treatments avoided
Sources -
https://grail.com/wp-content/uploads/2026/05/Pathfinder2_FactSheet_FINAL.pdf
https://grail.com/wp-content/uploads/2026/05/Giridhar.ASCO-2026.PF2-Primary.ORAL_FINAL-For-GRAIL-Website.pdf
https://grail.com/wp-content/uploads/2026/05/Swanton_ASCO-2026_NHS-Galleri_FINAL-Slides-05.26.2026.pdf
𝕏Both Prenuvo-Polaris and PATHFINDER 2 were both only in abstract form at ASCO , it seems. The jury is very much out atm.
𝕏This is PATHFINDER-2's ASCO '26 abstract. Adverse event rate is 5/35000, and no serious AE. https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA10509
𝕏🩸PATHFINDER-2 detected 4x ⬆️cancers with ctDNA MCED testing, but w/⤵️ advanced-stage
🫁 Divarasib and Elirasib ⬆️activity, hopes for chemo-free in KRAS➕.
🎯CAPTURE, capecitabine outperformed alpelisib + fulvestrant in PIK3CA-mutant #bcsm after CDK4/6 inhibitors. @ASCO
𝕏The other sleight of hand is the false-positive number. GRAIL leads with “specificity 99.6%, under 0.4% false positives,” which sounds flawless. But when you screen mostly healthy people, where cancer is rare, the number that matters is positive predictive value: when the test says “cancer signal detected,” how often is it right? About 60% in PATHFINDER 2 and 52% in NHS-Galleri. In plain terms, roughly 4 of every 10 people who get a positive result go through a full cancer workup, scans, biopsies, weeks of fear, and are ultimately told it was a false alarm. The test also misses most cancer overall, catching about a third, and it’s strongest at finding disease that has already advanced, the opposite of what screening is for.
And the question that decides everything is still open: does finding cancer this way help anyone live longer? Stage shift is a surrogate, and the cancer-specific mortality data from this trial are still being collected, years away. Catching something earlier is not the same as living longer.
Maybe some utility in monitoring response to treatment or recurrence? 🤷
The test is available commercially in the US for about 1000$ (annual). Would you get one? Have you had one?
Sources: NHS-Galleri primary results, ASCO 2026 (Swanton et al., NCT05611632). This is conference data, not peer reviewed yet.
𝕏
𝕏One blood test. One vial. Screening for 50 different cancers simultaneously.
It's called Galleri. And the FDA could approve it later this year.
Right now, we routinely screen for exactly five cancers in the United States — breast, colon, cervical, prostate, and lung. Each requires its own separate scan or exam. For the rest — pancreatic cancer, ovarian cancer, liver cancer, esophageal cancer, gastric cancer, and dozens more — we have no routine screening at all. We find them when symptoms appear. By then, most are Stage 3 or 4. By then, for many patients, it's too late.
Pancreatic cancer has a 12% five-year survival rate — because we almost always catch it late. Ovarian cancer: 50%. Liver cancer: 21%. These numbers aren't medical failures. They're detection failures. The treatments exist. We just find the disease after the window for those treatments has closed.
Galleri changes the math entirely.
Here's how it works. Every tumor — no matter where it is in your body — sheds tiny fragments of DNA into your bloodstream as cancer cells die and divide. These fragments carry specific methylation patterns — chemical signatures that are unique to cancer cells and different from the DNA your healthy cells release.
Galleri captures these fragments from a standard blood draw and reads their methylation patterns using next-generation sequencing and AI-driven analysis. The AI doesn't just detect whether cancer is present. It predicts where it's coming from — which organ, which tissue type — with over 90% accuracy in studies. One vial of blood tells your doctor: there's a cancer signal, and it's likely originating in your pancreas, or your lung, or your liver.
Your physician then orders targeted follow-up imaging to confirm or rule out the finding. Galleri isn't a diagnosis. It's a precision compass that tells your doctor exactly where to look.
The data is building fast.
GRAIL has now sold over 475,000 Galleri tests commercially under a special FDA designation. The NHS-Galleri trial — the largest randomized controlled trial of any multi-cancer detection test in history — enrolled over 142,000 people aged 50-77 in England. The primary endpoint — an overall reduction in late-stage cancers — was not met. But by the third year of annual screening, they found a 26% reduction in Stage IV cancers in key deadly types including pancreatic, liver, lung, and gastric. The test detected four times more cancers overall when added to standard screening — catching cancers that would otherwise have been found late or not at all.
The U.S. Pathfinder 2 study — 25,490 participants — showed similar positive signals and forms the basis of the FDA submission filed in January 2026.
Congress has already acted. The Nancy Gardner Sewell Medicare Multi-Cancer Early Detection Screening Coverage Act passed in February. If the FDA approves Galleri, Medicare will begin covering one test per year starting in 2028.
The current retail price is $950. Exact Sciences' competing test Cancerguard is $659. These prices will fall dramatically once FDA approval triggers insurance coverage and competition scales.
As a cardiologist, let me tell you why this matters far beyond oncology.
Cancer is now the number one killer of Americans over 50. Not heart disease. Cancer. And the patients I lose to cancer are often the same patients whose hearts I saved — patients who survived their cardiac event, optimized their metabolic health, and then received a late-stage cancer diagnosis that nobody screened for because no screening tool existed.
I've written on this platform about GLP-1 drugs reducing cancer metastasis by up to 50%. About personalized mRNA cancer vaccines cutting recurrence by 49%. About inflammation as the common root of heart disease and cancer. About AI detecting disease years before symptoms.
Galleri is the missing piece that connects all of it.
Detect the cancer early — with a blood test. Confirm it with AI-enhanced imaging. Treat it with personalized mRNA vaccines, targeted therapy, and GLP-1 drugs that may slow progression. Monitor response with liquid biopsy in real time.
That's not five separate breakthroughs. That's one integrated system of cancer prevention and treatment that didn't exist five years ago — and could be standard of care within five more.
The shift from reactive to proactive medicine — from "we found it too late" to "we caught it in time" — has been the central theme of everything I've written on this platform. Preventive cardiology. Advanced lipid testing. Inflammation detection. AI imaging. Gene editing.
Galleri applies the same principle to cancer. And it could save more lives than all of them combined.
One blood test. Fifty cancers. FDA decision expected this year.
Prevention is the new cure. And the science just took its biggest step yet.
https://open.substack.com/pub/afshine/p/one-blood-test-fifty-cancers-the?r=22fro&utm_campaign=post&utm_medium=web&showWelcomeOnShare=true
About the PATHFINDER-2 Trial
PATHFINDER-2 (NCT05155605) is the largest multi-cancer early detection interventional study conducted in North America to date. Sponsored by GRAIL, Inc., it enrolled 35,883 adults aged 50 and older with no clinical suspicion of cancer at 32 clinical sites across the United States and Canada, adding an MCED blood test — GRAIL’s investigational MCED-V2 device — to guideline-recommended screening (ClinicalTrials.gov NCT05155605; GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; FDA Executive Summary). The study builds on the earlier PATHFINDER cohort study (Schrag et al., Lancet 2023) and is designed as a registrational study: its 12-month primary analysis, presented by Dr. Karthik Giridhar of Mayo Clinic at the 2026 ASCO Annual Meeting (Abstract LBA10509), is a core component of GRAIL’s FDA Premarket Approval submission alongside data from the randomized NHS-Galleri trial. Participants will be followed for a total of 3 years.
The commercial Galleri test is a different device from MCED-V2 — the FDA cites differences in assay workflow, classifier, and bioinformatics pipeline — and its effectiveness in the FDA package was bridged by re-running Galleri on frozen plasma from a weighted subset of trial participants, while the FDA presents safety results from MCED-V2 and considers that primary safety analysis an approximate estimate of Galleri’s safety profile (FDA Executive Summary, Sept 2026). Because PATHFINDER-2 is single-arm, its results describe how the test performs when used in an intended-use screening population — positive predictive value, specificity, sensitivity, cancer signal origin accuracy, detection yield, and the safety of the diagnostic workup. It cannot, by design, show whether MCED screening shifts cancer stage versus a control group or improves survival; those comparative questions sit with the randomized NHS-Galleri trial and longer-term follow-up, a distinction several physician voices below emphasize.
Wanted to do a deep dive on the Pathfinder2 and NHS-Galleri tests but I am not up to doing it justice
— Paleoncologist (@PaleoOnc) Jun 22, 2026
Besides, neither are really published yet.
We just have some charts from presentations at major meetings
I will just make a few points and leave it at that
The NHS-Galleri is a great study that is also a major missed opportunity
Props to performing a RANDOMIZED study of 140,000 people !!! 70k in each arm
But the primary endpoint studied was “reduction in diagnosis of stage 3/4 disease.
This was an ambitious but reasonable endpoint. Those are hard to cure diseases.
But the missed opportunity was that they should have done an overall mortality endpoint.
This was the NHS and they could’ve followed these folks for a decade or longer to get a read on whether serologic screening really made a difference at the population level
They did not go there. Probably did not want to
The fans were disappointed that the study missed its primary endpoint - no net reduction in stage III/IV disease
So they pivoted to the secondary endpoint, reduction is stage IV disease. This is not inconsequential since most stage IV cancers are INcurable, while stage IIIs are potentially curable, albeit at low rates.
They showed a modest reduction in stage IV disease downstages to stage III - about 25% reduction. This is fair, but for 70,000 people tested, that means about 100 theoretical patients were downstaged. And since a lot of stage threes are still not cured, like, lets say 50-75% are NOT cured, that means we only saved 25-50 patients.
Wonderful if that was you, but we had to screen 70,000 people to save 25 - NNT about 2500. I am not sure that is much to brag about, especially when you work in cost.
In the US, they did Pathfinder2, which is NOT a randomized study, so we can’t really learn anything in a comparative sense. Also, it is only the 1st year of a 3-year study.
This is important and a credit to them, because the first year you do a screening test you are assessing “prevalence’ - that is the whole population level of a disease (as detected by the modality). It tends to be higher.
Once you complete the prevalence round, you are only picking up “new” cancers and this is a more rational metric. Once a screening program is up and running, it is the incidence of NEW cancers per interval (typically a year) that matters most.
But since the “total number of cancers” is higher than “the number of new per year” the value of a screening program declines after year one. So kudos to them for checking this.
But we are in year one with 2 years to go.
Unfortunately, beyond a rough estimate of sensitivity and specificity of the test, we will not learn much about the impact on the population at large from mass screening
And lastly, without real long term follow-up, it will be hard to tell the impact of “over diagnosis”
This is the odds of finding a clinically irrelevant cancer.
One that is really cancer, but was never going to harm the patient.
Like the Korean thyroid cancer study. All those thyroids removed, and no extra lives saved
Without long term follow up, we can’t know if the test truly “migrates” stage 3s and 4s down to 1s and 2s … or if we are just finding 1’s (mostly) and some 2’s that are not clinically important
What were the bottom lines
Slightly different results from NHS-Galleri (UK) vs Pathfinder2 (North America)
NHS-Galleri (all three rounds)
True positive - 937
False negative (misses) 2114
False positive - 864
True negative 193,231
Positive predictive value about 50%
Half learned of a cancer diagnosis thanks to the test
Half were misinformed and went off on a work-up that was solely caused by the test
And 2114 received a false negative.
That’s a lot - that means that you can’t stop regular screening.
On the US side, slightly different
True positive 173
False negative (misses) 267
False positive - 114
True negative - 31,453
Positive predictive value about 60%.
Better than the UK, but remember this is year one.
The numbers will change after years 2-3
I don’t feel like crunching the numbers for a cost-benefit analysis but this is how you need to look at it
Costs
Raw cost of the tests at a population level
Add costs of working up positives
Tally the number of people harmed by diagnostic intervention
Benefits -
Again, we really can’t get benefits without a proper long term comparison arm
But the benefits ought to be lives saved from the test and advanced cancer treatments avoided
Sources -
https://grail.com/wp-content/uploads/2026/05/Pathfinder2_FactSheet_FINAL.pdf
https://grail.com/wp-content/uploads/2026/05/Giridhar.ASCO-2026.PF2-Primary.ORAL_FINAL-For-GRAIL-Website.pdf
https://grail.com/wp-content/uploads/2026/05/Swanton_ASCO-2026_NHS-Galleri_FINAL-Slides-05.26.2026.pdf
Trial Methodology & Results
Study Design
Prospective, single-arm, interventional registrational study. MCED blood test (investigational MCED-V2 device) performed once and added to standard-of-care screening; participants informed of results, with protocol-recommended diagnostic evaluation guided by cancer signal origin for positives. 3-year active follow-up; primary analysis at 12 months (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; FDA Executive Summary).
Population
35,883 adults aged ≥50 with no clinical suspicion of cancer, enrolled at 32 North American sites with enrollment targets promoting age, sex, race and ethnicity diversity. Key exclusions: current diagnostic evaluation for suspected cancer; invasive or hematologic malignancy or cancer treatment within 3 years (ClinicalTrials.gov NCT05155605; GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis).
Test (Device)
In-trial: GRAIL’s investigational MCED-V2 device — targeted methylation sequencing of cell-free DNA to detect a shared cancer signal and predict cancer signal origin. The commercial Galleri test is a different device (assay workflow, classifier, bioinformatics pipeline), assessed by bridging on frozen trial plasma; Galleri is a prescription-only laboratory-developed test, not FDA approved or cleared (FDA Executive Summary; GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis).
Endpoints
Test performance in the intended-use population — positive predictive value, specificity, episode sensitivity, cancer signal origin accuracy, cancer detection rate — plus safety of the diagnostic workup and time to diagnostic resolution. No comparator arm; no survival or mortality endpoints (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis).
Presenting Author
Karthik Giridhar, MD, Mayo Clinic — oral presentation LBA10509, 2026 ASCO Annual Meeting, May 29–June 2, 2026, Chicago (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis). Principal investigator: Nima Nabavizadeh, MD (per GRAIL).
Registry & Status
NCT05155605 — active, not recruiting; 35,883 enrolled (actual). Conducted in the United States and Canada (ClinicalTrials.gov NCT05155605).
Test Performance — 12-Month Primary Analysis (MCED-V2, as run in-trial)
| Metric (MCED-V2 data) | Result | Detail |
|---|---|---|
| Positive predictive value | 60.3% | 173 cancers diagnosed among 287 participants with cancer signal detected |
| Specificity | 99.6% | False-positive rate <0.4% |
| Episode sensitivity — all cancers | 39.3% | Share of all cancers diagnosed within 12 months detected by the initial test |
| Episode sensitivity — 12 deadly cancer types | 69.8% | Prespecified group accounting for ~2/3 of cancer deaths |
| Cancer signal origin accuracy | 91.3% | Top-two CSO predictions among true positives |
| Cancer detection rate | 0.54% | 173 true positives / 32,007 performance-analyzable participants |
All values from the 12-month primary analysis presented at ASCO 2026, generated with the investigational MCED-V2 device (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; ASCO 2026 Abstract LBA10509). As a single-arm study, these metrics describe test performance only — they do not demonstrate stage shift versus a control group or a survival benefit.
Reconciling with the FDA package: PATHFINDER 2 figures reconcile the same way on both KOL Pulse GRAIL profiles — PPV 60.3% is the as-run MCED-V2 result (440 cancers among 32,007 analyzable, GRAIL 12-month primary analysis; the PPV itself is 173 cancers among 287 cancer-signal-detected participants), while PPV 77.0% is the bridged Galleri estimate (303 cancers, weighted N = 21,418, data cutoff Dec 31, 2024; sensitivity 35.0%, specificity 99.85%; FDA Executive Summary) — different devices and different analysis sets, never comparable head-to-head. The FDA also noted that “In general, for each cancer type with guideline recommended screening, the Galleri 12-month episode sensitivity was higher in individuals not eligible for screening than those eligible for screening” (FDA Executive Summary, Table 9; bridged Galleri data).
PPV 60.3% — 173 of 287 cancer signals confirmed as cancer (MCED-V2)Source: GRAIL PATHFINDER 2 Fact Sheet (ASCO 2026 primary analysis) →
Cancer Detection & Stage Distribution
During 12 months of follow-up, 440 participants were diagnosed with cancer: 264 (60%) screen-detected and 176 (40%) clinically detected. Adding the MCED-V2 test to USPSTF grade A/B recommended screening (breast, cervical, colorectal, lung) increased the number of screen-detected cancers roughly 6.5-fold; added to A/B/C screening (including prostate), roughly 3-fold — descriptive, single-arm comparisons. Of the new primary cancers diagnosed, 53% were stage I–II and 70.9% stage I–III; 67.6% of cancers detected were types with no USPSTF A/B/C screening recommendation (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; MCED-V2 data). Note: the 32,007-participant 12-month performance-analyzable set (ASCO 2026 fact sheet) and the 25,490-participant figure cited in GRAIL’s PMA announcement are different data snapshots/analysis sets.
~6.5x more screen-detected cancers when added to USPSTF A/B screening — descriptive, single-armSource: GRAIL press release, May 31, 2026 →
Safety of the Diagnostic Workup (MCED-V2 Primary Safety Analysis)
Among screen-positives, invasive follow-up was the norm, not the exception. Of 218 participants who underwent diagnostic evaluation for a positive MCED-V2 result, 159 (72.9%) had at least one invasive procedure. Among the 90 screen-positive participants with no cancer diagnosed within 12 months (false positives), 43 (47.8%) had at least one invasive procedure — including 4 surgical procedures and 33 endoscopies — and false positives waited longer for diagnostic resolution than true positives (median 75 vs 36 days) (FDA Executive Summary, Sept 2026; MCED-V2, DCO Dec 31, 2024). Of 227 invasive procedures performed in those 159 participants, 89.4% (203/227) were non-surgical per the FDA count; GRAIL’s fact sheet reports 90.5% nonsurgical in its own analysis set (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis).
At the population level, 0.6% of the 35,335 safety-analyzable participants underwent an invasive procedure such as a biopsy to evaluate a positive MCED result — a secondary, all-participant framing (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis). No serious study-related adverse events were reported during the diagnostic workup in the primary analysis; five study-related adverse events were reported overall. One serious adverse event related to the diagnostic workup was identified after data lock, with follow-up ongoing and full reporting planned in the next interim analysis. Median time to diagnostic resolution was 48 days per GRAIL’s fact sheet (46 days per the FDA analysis). Participant-reported anxiety rose temporarily with a positive result or cancer diagnosis and returned to pre-study levels by study end (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis; GRAIL Press Release, May 31, 2026).
72.9% of evaluated screen-positives had an invasive procedure; 47.8% of false positives (FDA, MCED-V2)Source: FDA Executive Summary (primary safety analysis, MCED-V2) →
Source: GRAIL PATHFINDER 2 Fact Sheet →
Dateline: posted June 20, 2026, citing the ASCO 2026 abstract — before the post-data-lock serious adverse event related to diagnostic workup was reported (GRAIL fact sheet / FDA Executive Summary). Quote verbatim and complete.
@YounisJoseph I really think the risk of so called unnecessary biopsy is overblown.
— Sean X. Luo MD PhD (@seanluomdphd) Jun 20, 2026
This is PATHFINDER-2's ASCO '26 abstract. Adverse event rate is 5/35000, and no serious AE. https://ascopubs.org/doi/10.1200/JCO.2026.44.17_suppl.LBA10509
FDA Review: PMA Under Evaluation — Not Approved
Galleri is not FDA approved
The Galleri test has not been cleared or approved by the FDA. It is available in the United States as a prescription-only laboratory-developed test performed in GRAIL’s CLIA-certified, CAP-accredited laboratory (GRAIL Fact Sheet, ASCO 2026 · 12-mo primary analysis). GRAIL submitted a Premarket Approval (PMA) application to the FDA on January 29, 2026 under Breakthrough Device Designation. The submission is anchored on test performance and safety results from 25,490 consented PATHFINDER-2 participants with one year of follow-up (a different data snapshot than the 32,007-participant 12-month ASCO analysis set), together with data from more than 70,000 participants in the intervention arm of the NHS-Galleri trial’s prevalent screening round (GRAIL press release, Aug 2026). Because the trials ran the investigational MCED-V2 device, Galleri’s effectiveness before the panel rests on bridged analyses (Galleri re-run on frozen trial plasma from a weighted subset), while the FDA presents safety results from MCED-V2 and considers that primary safety analysis an approximate estimate of Galleri’s safety profile (FDA Executive Summary, Sept 2026).
On September 23, 2026, the FDA’s Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee is scheduled to convene, discuss, and vote on the Galleri PMA — the FDA’s first advisory committee review of a multi-cancer early detection test (FDA.gov, Advisory Committee Calendar). The FDA’s briefing materials are already drawing physician discussion, including of per-cancer sensitivity figures — captured in the sentiment table below.
Source: FDA Advisory Committee Calendar →Source: GRAIL press release — FDA Advisory Committee announcement →
5/ The numbers, from FDA's summary. 12-month sensitivity 31.6% in NHS-Galleri, 35.0% in PATHFINDER 2. Stage I: 13.6% and 21.4%. Stage IV: about 60% in both. Prostate 10.7%. Breast 19-26%. And for every cancer that already has a screening test, Galleri did worse in people eligible for that test than in people who weren't - read that twice.
— Neil Vasan (@NeilVasan) Sep 21, 2026
PATHFINDER-2 in the News
PATHFINDER-2 FAQ
What is the PATHFINDER-2 trial?
PATHFINDER-2 (NCT05155605) is a prospective, single-arm registrational study by GRAIL, Inc. evaluating a multi-cancer early detection (MCED) blood test — run in-trial as GRAIL's investigational MCED-V2 device — added to standard-of-care screening in adults aged 50 and older with no clinical suspicion of cancer. 35,883 participants were enrolled at 32 sites across the US and Canada (ClinicalTrials.gov; 35,878 in the primary analysis population), making it the largest MCED interventional study in North America. Because it is single-arm, it measures test performance and safety — not survival or mortality outcomes.
What did PATHFINDER-2 show at ASCO 2026?
In the 12-month primary analysis (ASCO 2026, Abstract LBA10509), the in-trial MCED-V2 test had a positive predictive value of 60.3% (173 of 287 participants with a cancer signal were diagnosed with cancer), specificity of 99.6%, and cancer signal origin prediction accuracy of 91.3% (MCED-V2 data). Of 440 cancers diagnosed during 12 months of follow-up, 264 (60%) were screen-detected, and adding the test to USPSTF A/B screening increased the number of screen-detected cancers roughly 6.5-fold — a descriptive, single-arm comparison (GRAIL fact sheet).
What is MCED-V2, and how does it relate to Galleri?
MCED-V2 is the investigational device GRAIL actually ran in PATHFINDER 2 and NHS-Galleri. Per the FDA, 'The Galleri test is a different device from MCED-V2' — differences include the assay workflow, classifier, and bioinformatics pipeline. For the FDA review, Galleri performance was bridged: the Galleri test was re-run on frozen plasma from a weighted subset of trial participants, giving 12-month episode sensitivity 35.0%, specificity 99.85%, and PPV 77.0% (303 cancers, weighted N = 21,418, data cutoff Dec 31, 2024; FDA Executive Summary, Sept 2026). The FDA presents safety results from MCED-V2 and considers that primary safety analysis an approximate estimate of Galleri's safety profile; effectiveness results are presented for Galleri from the bridged frozen-plasma testing. The as-run MCED-V2 figures and the bridged Galleri figures come from different devices and analysis sets and should never be mixed.
Is the Galleri test FDA approved?
No. Galleri is not FDA approved or cleared; it is available in the US as a prescription-only laboratory-developed test (LDT) performed in GRAIL's CLIA-certified laboratory. GRAIL submitted a Premarket Approval (PMA) application to the FDA on January 29, 2026 under Breakthrough Device Designation, supported by PATHFINDER-2 and NHS-Galleri data. The FDA's Molecular and Clinical Genetics Panel advisory committee is scheduled to review the application on September 23, 2026 — the first FDA advisory committee review of an MCED test PMA.
How sensitive was the MCED test in PATHFINDER-2?
With the in-trial MCED-V2 device, episode sensitivity — the proportion of all cancers diagnosed within 12 months that the initial test detected — was 39.3% across all cancers and 69.8% for a prespecified group of 12 cancers that account for roughly two-thirds of cancer deaths (GRAIL fact sheet; MCED-V2 data). In the FDA's bridged Galleri analysis, 12-month episode sensitivity was 35.0% (FDA Executive Summary; bridged Galleri data). The test is intended as an addition to, not a replacement for, guideline-recommended screening.
How is PATHFINDER-2 different from NHS-Galleri?
PATHFINDER-2 is a single-arm North American interventional study of 35,883 adults measuring real-world test performance and safety; it has no comparator arm. NHS-Galleri (NCT05611632) is a randomized controlled trial of more than 142,000 UK adults testing whether annual MCED screening (also run with the investigational MCED-V2 device) reduces late-stage cancer diagnoses; its primary endpoint (reduction in stage III/IV diagnoses) was not met, with a prespecified secondary reduction in stage IV diagnoses reported. Both datasets support GRAIL's FDA PMA submission for the Galleri test.
Key KOL Sentiments — PATHFINDER-2
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated September 21, 2026. Tweet text is reproduced verbatim and in full from each physician’s public post; every clinical statistic on this page is labeled with its source (GRAIL press release and fact sheet, ASCO 2026 Abstract LBA10509, ClinicalTrials.gov, FDA.gov / FDA Executive Summary). In-trial results were generated with GRAIL’s investigational MCED-V2 device; FDA-package Galleri figures are bridged estimates from frozen trial plasma — the two are labeled and never mixed. PATHFINDER-2 is a single-arm study: no comparison-based or survival conclusions are drawn on this page. The Galleri test is not FDA approved.