By Joshua Ofman MD, MSHS, GRAIL President; Megan P. Hall Ph.D., GRAIL Medical Affairs; Christina Clarke Dur Ph.D. GRAIL Cancer Epidemiology

Multi-cancer early detection (MCED) tests hold enormous promise, but will only achieve their public health and clinical impact if the tests are validated rigorously in the appropriate “intended use” population: adults at elevated risk with no clinical suspicion of cancer.

While there are several MCED tests in the discovery and development phase, we believe that no cancer screening test should be introduced into clinical practice until its performance has been prospectively validated in the intended use population. The Food and Drug Administration (FDA) has announced a similar approach for how safety and effectiveness is established for diagnostic tests (Note 1). GRAIL’s GalleriⓇ MCED test was not launched until the PATHFINDER study, which was conducted under an FDA-approved investigational device exemption application, confirmed Galleri’s performance in the intended use population: adults aged 50 and above with no clinical suspicion of cancer (Schrag 2023). Clinical validation from an interventional study in the intended use population must not be confused with analytical or basic validation from confirmatory sample sets in discovery and development studies. 

Why is clinical validation in the intended use population so important for cancer screening? 
For certain MCED tests in development, promising performance in retrospective case-control studies has not consistently been confirmed by trials in the intended use population evaluating performance in clinical practice. Retrospective case-control studies may have significant study design flaws. For example, studies may be small, have cases and controls that are highly selected and not representative of cancer prevalence in the general population, or are not appropriately “matched” – e.g., the samples are from different times, different clinics or health systems, and/or patients of different ages. These limitations can lead to non-reproducible results, which may include detecting study artifacts rather than cancer, not clearly distinguishing (or even combining) training and validation sample sets, batch effects (differences in sample handling and machine conditions), or other technical artifacts. This has been observed previously with ovarian cancer tests (e.g., Petricoin 2002, Baggerly 2005) and other early MCED technologies (e.g., Cohen 2018, Lennon 2020). For example, the original CancerSEEK assay is a case-control study that reported a specificity of greater than 99% (Cohen 2018). However, when studied in a clinical trial in the intended use population, the specificity of the first blood test was 95.3% (at least a 4.7 times higher false-positive rate), with a positive predictive value (PPV) of 5.9% (Lennon 2020). 

Unfortunately for the MCED field, some test developers are claiming results from small, retrospective case-controlled studies as “validation” with no reported plans for prospective studies in the intended use population (Abraham 2025, Seeking Alpha). The results of such studies may appear promising at first glance, but they should not be considered validation for real-world screening readiness. There is simply no way to establish a test’s safety or benefits until clinical validation performance has been established in the intended use population. 

If tests without sufficient validation are prematurely offered and result in patient harm, the entire field of MCED could be set back, which has the potential to dramatically impact public health. Harms to individual patients may result from missing deadly cancers, the risks of excessive diagnostic follow-ups resulting from tests with high false-positive rates, and the risk of over-diagnosing indolent cancers. The only way to understand, quantify, and minimize these patient risks is by ensuring that any test introduced into clinical practice has been adequately and rigorously validated with strong performance characteristics in the intended use population. 

The first clinically introduced MCED test – Galleri – is supported by strong, published results from large and well-designed case-controlled studies, interventional trials, and real-world studies in the intended use population (Klein 2021, Schrag 2023, Atwood 2024). Specifically, the Galleri test’s robust specificity and cancer signal origin (CSO) accuracy in two of the largest and most diverse trials ever conducted in cancer screening, including the first and only MCED randomized controlled trial, has confirmed what was observed in earlier studies (Klein 2021, Schrag 2023, Giridhar 2024, Neal 2022, GRAIL 2025 [1], GRAIL 2025 [2]). Importantly, the PPV substantially increased in these larger and more representative trials (GRAIL 2025 [1], GRAIL 2025 [2]) and cancer detection rates were substantially higher when added to standard of care (SOC) screening in PATHFINDER 2 compared to PATHFINDER (GRAIL 2025 [2]). The results of this breakthrough technology and the education of the clinical community have helped catalyze the entire MCED field. However, the MCED field is at risk if other MCED tests are launched without the same approach to validation and without rigorously demonstrating a favorable benefit-risk profile. 

Cancer is soon to become the leading killer worldwide, and the current status quo of cancer screening is unacceptable. We only look for three cancers in women (breast, colon, and cervical), two in men (colon and prostate), and leverage an additional screen (lung) for heavy smokers (Nicholson 2024, Davidson 2021, Krist  2021, Curry SJ 2018, Grossman DC 2018). While these screening tests are saving lives, we recently estimated with the American Cancer Society that nearly 80% of cancer deaths result from all of the other cancers we are not screening for today (Ofman 2025) – there is no mechanism to detect those cancers before symptoms appear, when cancers are more treatable and outcomes are better. The SOC screening paradigm only identifies 14% of cancers in the population (Ofman 2025) in the U.S. Adding the Galleri test to SOC screening could dramatically increase the cancer detection rate in the population (Hackshaw 2021) without increasing the risk of over-diagnosis (Chen 2020, Swanton 2025). In the PATHFINDER trial in the intended use population, adding Galleri to SOC more than doubled the number of cancers detected, with half being in stages 1 or 2 (Schrag 2023).

It is quite apparent that not all MCED tests are created equal. For this reason, any comparison of test performance must be evidence-driven and based on the study design, as we describe below (Note 2). For example, it would be clinically inappropriate to compare the results from a case-control study against those from an interventional study. 

To realize the tremendous promise of MCED tests, and continue to develop this important field, all test developers must be held to high standards. Our families, our loved ones, and patients are depending on us. 

Note 1: FDA Guidance Documents Supporting Methodologies and Expectations for Clinical Validation 

Design Considerations for Pivotal Clinical Investigations for Medical Devices

“Sites from which subjects or samples are chosen for studies that support the intended use of the device should be representative of the types of sites where the device is intended to be used. Subjects or samples should also represent the proposed target population. Estimates of overall performance from non-representative sites or subjects may suffer from selection bias.” 

Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests

“We note at the outset that evaluation of a new diagnostic test should compare a new product’s outcome (test results) to an appropriate and relevant diagnostic benchmark using subjects/patients from the intended use population; that is, those subjects/patients for whom the test is intended to be used.” 

In Vitro Diagnostic (IVD) Device Studies – FAQs

“Studies should be performed in a representative sample of the intended use population (i.e., representation of both diseased and non-diseased cases, and controlling for subject demographics and morbidity factors that may affect the level of device performance).”

Note 2: A Checklist for Careful Evaluation of Blood-Based MCED Studies

There are important considerations when evaluating the results of an MCED study or comparing results between studies. 

  1. What was the study design? Well-designed case-control studies, in which cancer patients are tested after diagnosis, can provide estimates of “test sensitivity.” Interventional studies in the intended use population provide estimates of “episode sensitivity,” because patients are followed for a defined time period to understand what cancers may have been missed by the test, and whether apparent false positive test results actually precede a cancer diagnosis. Performance that is applicable to actual clinical use should be assessed in the intended use population and comparisons should not be made across different study designs. 
  2. In an interventional study, what is the length of the episode? Interventional studies define an episode duration (e.g., 12 months to define the cancer status) to estimate episode sensitivity. Studies with different episode durations may have different sensitivity estimates and are difficult to compare and cannot be compared to estimates of test sensitivity from case-controlled studies.  
  3. Were the sensitivity estimates reported at the same specificity? Any estimates of test sensitivity must be compared in relation to the reported levels of specificity. For example, a 98.5% specificity has a 3x higher false positive rate than a specificity of 99.5%. With a lower specificity, a test would be expected to have a higher sensitivity estimate, all other factors held constant.  
  4. What is the overall cancer incidence and case mix in the study population? Overall cancer incidence rate over the episode may be influenced by the percentage of cancer survivors or other high-risk groups. Cancer case mix is one of the most important study characteristics for interpreting performance. If a population is rife with indolent forms of breast and prostate cancer or late-stage cancers versus more deadly cancers across all stages, the performance characteristics will be very different. Studies that exclude certain cancer types should not be directly compared to studies with a different case mix of cancers, as this will impact the results. 
  5. In the interventional studies, what was the intensity and timing of guideline-based screening or imaging? This will have an impact on the results. 
  6. What is the extent of the healthy volunteer effect? In screening trials, it is usual to have participants who are healthier than the general population, with lower overall cancer incidence rates and higher adherence to guideline-based screening. This can impact the cancer case mix. It is generally appropriate to standardize the cancer case mix to that of a standard population (e.g., SEER) to generate estimates of performance that can be more easily compared across different study populations.
  7. Finally, are the results reported from the MCED blood test itself, or from a combination of tests? (e.g., blood test + PET-CT) 

References:

Abraham, J., Domenyuk, V., Perdigones, N. et al. Validation of an AI-enabled exome/transcriptome liquid biopsy platform for early detection, MRD, disease monitoring, and therapy selection for solid tumors. Sci Rep 2025;15:21173 doi:10.1038/s41598-025-08986-0.

Atwood C, Moy S, Kindy MS, et al. REFLECTION: Initial Findings From a Real-World Evidence Study of Multi-Cancer Early Detection (MCED) and Toxic Exposures Among Veterans in the Veterans Affairs Healthcare System (VA). Poster and Presentation at the Early Detection of Cancer Conference (EDCC); October 22-24, 2024; San Francisco, CA.

Baggerly KA, Coombes KR, Morris JS. Bias, Randomization, and Ovarian Proteomic Data: A Reply to “Producers and Consumers. Cancer Informatics 2005;1. doi:10.1177/117693510500100101.

Chen X, Dong Z, Hubbell E, et al. Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA. Clin Cancer Res 2020;27(15): 4221–4229. doi:10.1126/science.abb9.

Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 2018;359(6378):926–930. 

Curry SJ, Krist AH, Owens DK, et al. Screening for Cervical Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2018;320;(7):674-686. doi:10.1001/jama.2018.10897.

Davidson KW, Marry MJ, Mangione CM, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2021;325;(19):1965-1977. doi:10.1001/jama.2021.6238. 

Giridhar KV, Demeure MJ, Kim RH, et al. PATHFINDER 2: A Prospective Study to Evaluate Safety and Performance of a Multi-Cancer Early Detection Test in a Population Setting. Cancer Res 2024;84(6_Supplement):4784. doi.org/10.1158/1538-7445.AM2024-4784.

GRAIL, Inc. [1] (2025, May 13). GRAIL Reports First Quarter 2025 Financial Results [press release]. https://grail.com/press-releases/grail-reports-first-quarter-2025-financial-results/

GRAIL, Inc. [2] (2025, June 18). GRAIL Announces Positive Top-Line Results From The Galleri® PATHFINDER 2 Registrational Study [Press release]. https://grail.com/press-releases/grail-announces-positive-top-line-results-from-the-galleri%e2%93%a1-pathfinder-2-registrational-study/

Grossman DC, Curry SJ, Owens DK, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2018;319;(18):1901-1913. doi:10.1001/jama.2018.3710.

Hackshaw A, Cohen SS, Reichert H, Kansal AR, Chung KC, Ofman JJ. Estimating the population health impact of a multi-cancer early detection genomic blood test to complement existing screening in the US and UK. Br J Cancer 2021;125(10):1432-1442. doi: 10.1038/s41416-021-01498-4.

Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol 2021 Sep;32(9):1167-1177. doi: 10.1016/j.annonc.2021.05.806.

Krist AH, Davidson KW, Mangione CM, et al. Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2021;325;(10):962-970. doi:10.1001/jama.2021.1117.

Lennon AM, Buchanan AH, Kinde I, et al. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science. 2020 Jul 3;369(6499):eabb9601. doi: 10.1126/science.abb9601. Epub 2020 Apr 28.

Neal RD, Johnson P, Clarke CA, et al. Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial. Cancers 2022;14(19):4818. doi: 10.3390/cancers14194818.

Nicholson WK, Silverstein M, Wong JB, et al. Screening for Breast Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2024;331;(22):1918-1930. doi:10.1001/jama.2024.5534.

Ofman JJ, Dahut W, Jemal A, Chang ET, Clarke CA, Hubbell E, Kansal AR, Kurian AW, Colditz GA, Patel AV. Estimated proportion of cancer deaths not addressed by current cancer screening efforts in the United States. Cancer Biomark 2025 Jan;42(1):18758592241308754. doi: 10.1177/18758592241308754. Epub 2025 Mar 20. PMID: 40109213.

Petricoin EF, Ardekani AM, Hitt BA, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;;359(9306):572-7. doi: 10.1016/S0140-6736(02)07746-2.

Schrag D, Beer TM, McDonnell CH, et al. Blood-based tests for multi-cancer early detection (PATHFINDER): a prospective cohort study. Lancet 2023;402:1251-1260. doi: 10.1016/S0140-6736(23)01700-2.

Swanton C, Cohn A, Margolis M, et al. Prognostic significance of blood-based multi-cancer detection in circulating tumor DNA (ctDNA): 5-year outcomes analysis. J Clin Oncol 2025;43(suppl 16).doi: 10.1200/JCO.2025.43.16_suppl.101.

This Statement has been prepared in accordance with paragraph 22(2) of Schedule 19 of the UK Finance Act 2016 for the financial year ending December 31, 2024.

How GRAIL manages UK tax risk

GRAIL seeks to be as compliant as possible with local tax legislation, worldwide tax regulations, and corporate social responsibility.  We seek to report and pay the fair amount of tax due, in the appropriate jurisdiction, at the correct time. This is part of GRAIL’s desire to build trust in the tax system amid a period of large-scale international tax reform. GRAIL will not engage in artificial activity purely for tax purposes.  

GRAIL’s attitude towards tax planning

GRAIL’s goal is to fully and accurately comply with our tax obligations with the highest integrity.

Where material uncertainty exists in any area of its business, GRAIL seeks advice to ensure that it is fully compliant with applicable laws.

GRAIL will uphold the applicable tax laws in each country of operation through non-abusive methods of practice and therefore aim to be compliant both with the law as written and the law’s intended effects, where known.

The level of risk that GRAIL is prepared to accept for UK taxation

Rather than fixing set thresholds for acceptable UK tax risk, GRAIL assesses risk on a case-by-case basis based on the relevant facts and circumstances, within the context of the business activities and with the assistance of external advisers where appropriate.

GRAIL’s approach towards its dealings with HMRC

GRAIL seeks to remain transparent and to establish a constructive relationship with HM Revenue & Customs (“HMRC”).  Additionally, we will proactively engage with HMRC, in order to build trust and to reduce uncertainty and risk. GRAIL is cooperative and is committed to working collaboratively with all taxing authorities.

We believe screening individuals for many types of cancer with a multi-cancer early detection (MCED) test represents a significant opportunity to reduce the burden of cancer. Today, with a unanimous vote to advance the “Nancy Gardner Sewell Medicare Multi-Detection Early Detection Screening Coverage Act,” the House Committee on Ways and Means took an important step on the path to ensuring Medicare beneficiaries and their doctors can access these innovative screening tests once they are FDA-approved. While this is a necessary legislative step, in order to become law the bill would have to be passed by the House and the Senate, and then signed into law by the President.

GRAIL stands with the policymakers and cancer community leaders who are working to ensure, through legislation, that Medicare beneficiaries — who have the highest risk for cancer due to age — do not face unnecessary barriers to access.

We believe screening individuals for many types of cancer with a multi-cancer early detection (MCED) test represents a significant opportunity to reduce the burden of cancer.  However, without Congressional action, Medicare beneficiaries and their doctors may face significant delays in accessing these innovative screening tests once they are FDA-approved.  Led by the American Cancer Society’s Cancer Action Network and the Prevent Cancer Foundation, a group of 52 national advocacy organizations today shared their enthusiastic support for meaningful, timely access to MCED technologies and their endorsement of advancing this legislation with its associated policy updates.  GRAIL stands with the policymakers and cancer community leaders who are working to ensure, through legislation, that Medicare beneficiaries — who have the highest risk for cancer due to age — do not face unnecessary barriers to access. 

View the presentation deck here.

To read the blog post from NHS England, click here.

The NHS-Galleri trial, which started enrolling participants in 2021, was designed to inform implementation of the Galleri test as a national screening programme if recommended by the UK National Screening Committee on the basis of the final study results, which are expected in 2026. The trial was designed with three consecutive years of screening in order to achieve the primary endpoint, which is the absolute reduction in the number of late stage (Stage III and IV) cancer diagnoses. 

As described in March, NHS England planned to look at a snapshot of selected first year results (the prevalent screening round with one year of follow-up) from the NHS-Galleri trial to assess whether there is enough compelling early evidence to initiate a pilot of Galleri within the NHS setting. This first year analysis was conducted solely to determine whether there was an early sign of compelling patient benefit, sufficient for the NHS to accelerate an implementation before the final study readout. Three robust, ambitious and pre-specified criteria were assessed: the positive predictive value (PPV) of the Galleri test, the number of late-stage cancers detected and the total number of cancers detected in the intervention arm compared with the control arm. Notably, this was not an interim analysis of the trial primary endpoint, as that analysis requires data from all three rounds of screening.

Based on a snapshot of first-year results from the ongoing NHS-Galleri trial, NHS England has decided to await final results from the three-year trial before determining whether to initiate a pilot of the Galleri test in the NHS.

Advised by a multidisciplinary expert panel, NHS England determined that, while the early analysis showed that the assessed clinical performance of Galleri was very promising — consistent with or better than Galleri’s clinical performance observed in previous published studies — there is not yet enough early compelling evidence to accelerate implementation through a pilot programme at this stage.

As described by the NHS, “Committing to accelerate implementation of the test in the NHS at scale would have been an exceptional step, requiring exceptional data after just one year, and while what we have seen is very promising, the data so far do not support moving at such a fast pace.” Instead, NHS England will make a decision on the basis of the final trial results, expected in 2026. 

This early look at certain selected metrics provides only a limited view. As demonstrated in previous cancer screening trials, results from the first screening round do not always reflect the final results, especially for reduction in late stage diagnosis. In the US National Lung Screening Trial (NLST) for example, participants underwent three annual screenings. Ultimately, the trial demonstrated a significant relative reduction in mortality for those who received low-dose CT screening. However, no reduction in stage IV cancers was observed after the first year of screening. This is because a prevalent screening round often includes many asymptomatic cancers in later stages that have not been ‘swept out’ by that first year of screening. In NLST, the stage IV incidence was reduced after that first year of screening – and was maintained throughout the follow-up period. 

The NHS-Galleri trial – like numerous other cancer screening trials – was designed with multiple years of screening, and thus it remains important to complete the trial and evaluate the primary objective and endpoints at the end of the study. 

Diagnosing more cancers before they present symptomatically is central to GRAIL’s mission and is also a core part of NHS England’s Long Term Plan to transform cancer outcomes. NHS England has reiterated its belief that multi-cancer early detection is an important innovation that could become a core component of its ambition to reduce late-stage cancer diagnosis in the future.

The NHS-Galleri trial completes appointments with the final blood samples being taken in July 2024 and the ongoing involvement of participants (and any subsequent diagnostic follow up in the NHS) remains critical to fully understanding the test’s potential benefit at population scale. We await the final results and I would like to reiterate my sincere appreciation to the more than 140,000 participants who generously volunteered to take part in the trial to contribute to, and advance, this valuable field of science and medicine. 

GRAIL remains focused on our mission to detect cancer early, when it can be cured.

Revenue for the first quarter of 2023, comprised of Galleri test sales and biopharmaceutical partnerships revenue, was $26.7 million. 

We continue to see uptake for Galleri in health systems, clinics and the employer and life insurance channels across the U.S. We surpassed 10,000 Galleri prescribers in early 2024, and we have completed more than 180,000 commercial Galleri tests cumulatively as of the end of March. With forward leaning payors and employers across a multitude of sectors, commercial engagements remains strong. 

Our registrational clinical studies are progressing. The NHS-Galleri study is anticipated to complete its third and final round of planned blood draws in July, and we have enrolled more than 30,000 participants in our PATHFINDER 2 study. Study results for NHS-Galleri are anticipated in 2026. Interim results from PATHFINDER 2 are expected in 2025 when we have a full year follow-up on the first 25,000 patients. Together, these studies are anticipated to include approximately 175,000 participants and support our PMA submission to the FDA. 

Additionally, the Galleri-Medicare study (REACH) will enroll 50,000 Medicare beneficiaries for three annual tests, evaluating the performance and clinical impact of Galleri compared to a matched synthetic control. This study is an important addition to our body of clinical and real-world evidence for multi-cancer early detection.

We continue to pursue potential applications for our technology in precision oncology settings and recently announced a novel risk-classification assay to be included in a lung cancer study in collaboration with AstraZeneca. Data evaluating our methylation technology’s capability in molecular subtyping were recently presented at the American Association for Cancer Research (AACR) Annual Meeting 2024. 

Recent Business Highlights

In the precision oncology setting, we shared data illustrating the potential adaptability of our methylation platform in identifying cancer histological and molecular subtypes through blood samples. 

Cancer accounts for just over a quarter of all deaths in England in a typical year. The NHS Long Term Plan (LTP) was published in January 2019 and set out stretching ambitions and commitments to improve cancer outcomes and services in England in the following ten years. Earlier and faster cancer diagnosis are among its central ambitions.

It is with considerable humility, but also great pride, that I have the honour of working for a company, GRAIL, which has embarked on an extraordinarily challenging mission to find many types of cancer earlier, before symptoms appear, when there are more treatment options, and a greater potential for cure. 

Galleri® , GRAIL’s multi-cancer early detection (MCED) test, has been assessed in published case-control and interventional studies in the intended use population. The results demonstrate consistent findings throughout, and Galleri is now the subject of real world evidence generation and the largest prospective randomised controlled trial of an MCED test ⎯ the NHS-Galleri trial conducted in England. 

Traditionally, cancer screening programmes have taken a decade or more from publication of effectiveness to be implemented on a population-scale. This means that, including the duration of clinical trials, it has historically taken some 20-30 years from having a validated technology  to achieving broad benefits for patients and society. With the rapidly growing burden of cancer ⎯ it is soon to become the world’s biggest killer ⎯ and the pace of technology change, many experts believe this paradigm must change.

As set out in a recent letter from NHS England to the Lancet, the NHS is keen for its patient population to benefit as quickly as possible from new, safe and effective technologies where there is an urgent unmet need, such as with late cancer diagnosis. Therefore, in addition to the long-term aim, NHS England plans to look at a snapshot of selected first year results (the prevalent screening round with one year of follow-up) from the NHS-Galleri trial to assess whether there is enough compelling early evidence to initiate a ‘pilot’ of up to one million tests within the NHS setting. This type of ‘in-service evaluation’ would offer a Galleri test to a similar ‘asymptomatic’ population as the trial. As well as generating real-world data to supplement the trial evidence, this pilot opportunity would allow the NHS to learn about how best to implement a multi-cancer screening programme rapidly. 

NHS England will base its decision on robust, demanding, pre-specified criteria, including the positive predictive value (PPV) of the Galleri test, the number of late stage cancers detected, and the total number of cancers detected in the intervention arm compared with the control arm. Notably, this is not an interim analysis of the trial primary endpoints, as any such analysis requires data from all three rounds of screening. The pilot will only proceed if the early results are exceptionally compelling enough to begin implementing a pilot program before the trial completes and the final results are known. Similarly, these results will only be made public should the pilot proceed, in order to place necessary focus on the integrity of the ongoing trial. 

Importantly, the early look at certain selected metrics will provide only a limited view, which may or may not be seen in the final results in 2026. Early results from cancer screening trials do not always reflect the final results, and often do not tell the whole story. The National Lung Screening Trial, for example, provides a salutary example: participants similarly underwent three annual screenings. Ultimately, the trial demonstrated a significant relative reduction in mortality for those with low-dose CT screening. However, no reduction in stage IV cancers was observed after the first year of screening because it was a prevalent screening round. This is because a prevalent screening round includes many asymptomatic cancers in later stages that have not been ‘swept out’ by that first year of screening. As expected, in NLST the stage IV incidence reduced after that first year of screening – and was maintained throughout the follow-up period. Crucially, the trial also demonstrated a 20% relative reduction in mortality that was maintained throughout the longer-term follow-up period. The NHS-Galleri study design and primary endpoints accept this ‘prevalent screening round effect’ and acknowledge that assessing a lasting reduction in late-stage disease requires multiple years of screening to ‘sweep out’ those later stage cancers.

Working in partnership with NHS England, world-class statisticians, epidemiologists and clinicians, we designed the 140,000 person NHS-Galleri trial to include three successive rounds of Galleri screening in addition to standard screening for those in the intervention arm, compared to a control group only receiving standard screens. This trial was conducted with a view to informing eventual implementation of Galleri within a national screening programme if recommended by the UK National Screening Committee.To ensure a representative, diverse population was recruited, we employed a fleet of mobile clinics staffed with phlebotomists, to enable access for participants in places with access challenges to health clinics ⎯ from ethnically and socioeconomically diverse cities to remote rural outposts. This approach had the additional benefit of not burdening overstretched GP surgeries, not least as the bulk of the recruitment took place during the COVID-19 pandemic in 2021. 

The active period of the NHS-Galleri trial comes to an end with the final blood draw anticipated to take place in July 2024. The primary objective of the trial is to demonstrate that the use of Galleri, alongside standard of care, can lead to a significant reduction in the incidence of late stage cancers ⎯ in-line with the UK’s overall goal of increasing the proportion of early-stage cancers detected. This will require an assessment of the data accumulated following all three annual rounds of screening, and it is expected that this analysis will be completed in 2026. Exploratory mortality analyses and modeled mortality based on observed stage-shift will also be undertaken, as well as longer term follow-up via national centralised data collection.  Planned, comprehensive health economic evaluation and analysis will provide necessary cost-effectiveness data.

We hope that NHS-Galleri will demonstrate highly compelling early evidence from which the NHS is able to make a decision to move forward with the proposed Multi-Cancer Blood Test Programme so that more patients can benefit more quickly. Such a pilot, if so agreed, would provide a suitable balance between being able to learn valuable implementation lessons to fulfill an unmet need rapidly, with the subsequent further decision dependent on longer-term measures of effectiveness. Whether or not a pilot is undertaken, for any number of reasons, GRAIL would continue to request that the UK National Screening Committee makes a decision about a population screening programme in due course, based on the final study results and full economic evaluation. We look forward to the NHS’s assessment of the early results in the coming months.

GRAIL continues to execute on our strategy towards population scale early cancer detection, and we are pleased with our progress in building the market for Galleri, driving our robust evidence generation programs and advancing future product development.

Revenue for the fourth quarter of 2023 was $30 million and for the full year 2023 was $93 million, comprising Galleri test sales and biopharmaceutical partnerships revenue. Full year revenue increased 68% in 2023 as compared to 2022. 

Galleri adoption continues to grow, with more than 9,000 ordering providers and more than 150,000 commercial tests completed as of year end 2023. We have established early commercial leadership in multi-cancer early detection (MCED) and secured coverage of Galleri with several forward-leaning payers and self-insured employers in various sectors, such as technology, healthcare, life insurance, and financial industries. 

We were pleased to announce the groundbreaking Galleri-Medicare study (REACH), which will enroll 50,000 Medicare beneficiaries and evaluate the clinical impact of Galleri compared to a matched synthetic control. Findings will add to our robust body of evidence evaluating the potential for MCEDs to change the future of cancer detection, particularly in diverse populations. Medicare will cover the costs of Galleri and related and routine items and services for study participants. The Galleri-Medicare study will further enhance our expansive clinical evidence program, which includes our pivotal NHS-Galleri randomized clinical trial, bringing planned enrollment to more than 385,000 participants. We are in the final round of blood draws for the NHS-Galleri trial and expect to complete final study visits in the third quarter of this year. 

GRAIL’s proprietary targeted methylation platform combined with our growing body of clinical and real-world data provide us with unique insights into cancer biology that enable product improvements and new product introductions over time. Potential applications for our technology in a precision oncology setting include pre-treatment prognosis, post-treatment prognosis or minimal residual disease (MRD), recurrence and clinical monitoring, and novel biomarker discovery.

Recent Business Highlights

2023 was an exciting year for GRAIL. We are seeing continued strong early adoption of GalleriⓇ, our multi-cancer early detection (MCED) blood test, surpassing 150,000 commercial tests completed. Real-world use of Galleri has detected some of the most aggressive cancers in early stages, including endometrial, esophageal, gastrointestinal stromal, head & neck, liver, pancreatic and rectal cancers. For the majority of these cancer types, there are no alternative screening options available. We are passionate about our mission to detect cancer early, when it can be cured, and energized by the powerful stories we have heard from patients who have benefited from Galleri and from physicians and health systems who are successfully implementing Galleri into their practice. 

As an early leader in the field, we continue to establish strong relationships within the cancer and primary care communities, including collaborations with academic and community medical centers, opinion leaders, policy and advocacy groups. We are building on our clinical evidence program, and announced in December the Galleri-Medicare study (REACH), bringing planned enrollment for our clinical research programs to more than 385,000 participants. We were also pleased to publish results from our seminal PATHFINDER and SYMPLIFY studies in 2023 in The Lancet and The Lancet Oncology, respectively—two premier medical journals.

Cancer is a major public health crisis, and we are looking to a future where we can detect more cancers through screening, before symptoms arise, which we believe will ultimately save lives and reduce costs of care. Galleri works by detecting DNA fragments shed into the bloodstream by tumor cells. Cancer DNA has specific methylation patterns that can be used to both identify a shared cancer signal and localize that signal to a specific organ or tissue type. Galleri remains the only validated MCED test available for detection of a shared cancer signal across more than 50 cancer types. 

GRAIL’s proprietary targeted methylation platform, which underlies Galleri, and our growing body of clinical and real-world data, provide us with unique insights into cancer biology that enable product improvements over time, and the development of other products beyond asymptomatic cancer screening. Potential applications for our technology in a precision oncology setting include pre-treatment prognosis, post-treatment prognosis or minimal residual disease (MRD), recurrence and clinical monitoring, and novel biomarker discovery. We are leveraging a range of ongoing collaborations with leading academic oncologists and pharmaceutical companies to further develop these product opportunities.

In 2023, GRAIL continued to build on our key strengths:

Galleri has established early commercial leadership in MCED 
We are pleased to report that, to date, we have established over 100 commercial partnerships, including leading employers, payors, life insurance providers and health systems, such as HCA Healthcare—the largest health system in the U.S. Through these partnerships, we have also secured coverage of Galleri with several forward-thinking self-insurers in various sectors such as technology, healthcare, entertainment, life insurance, and financial industries.  

We have established a network of more than 9,000 ordering healthcare providers in the pre-reimbursement setting, with prescribers in private practices across the United States. We are encouraged by the consistency of the cancer signal detection rate we are seeing in commercial implementation with what we have observed in our clinical studies. We continue to build the key components of our commercial and laboratory infrastructure and capabilities that are required to support rapid, population-scale testing in a reimbursed environment.

We have worked closely with providers to develop and roll-out a suite of services to ensure that patients with a Galleri positive cancer signal, and their health care providers, are supported through the confirmatory diagnostic process.

Healthcare providers are offered direct support from our medical science liaisons and access to a specialized Galleri experience council—a cohort of physicians with Galleri experience (including experts from National Cancer Institute-Designated Cancer Centers) who can provide peer-to-peer consultations. We also operate an early cancer detection board that includes third-party experts across specialties to provide consultative advice for any challenging cases. 

For patients with a Galleri positive test result, we offer a support center that provides materials explaining the cancer signal detected result that can be shared with health care providers managing follow-up diagnostic evaluation. 

We are driving critical scientific and clinical research in the field
We have undertaken a rigorous approach to identify the informative cfDNA-based markers of cancer through what we believe is the largest clinical program in genomic medicine. Our robust clinical development program consists of studies that are planned to collectively include more than 385,000 participants, of which more than 300,000 have already been enrolled, and includes case-controlled, observational, interventional and real-world studies. 

In 2023, we reported final data from two key studies. Together with leading experts in the field, we published seminal results from the interventional PATHFINDER study in asymptomatic patients in The Lancet and from the SYMPLIFY study – the first prospective study of an MCED test in a symptomatic patient population – in The Lancet Oncology. Overall throughout the year, we published more than 20 manuscripts in clinical and scientific journals and more than 50 abstracts at renowned global congresses, including the American Association of Cancer Research (AACR), American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO).

We also completed second year study visits for the NHS-Galleri trial with a high retention rate of 91.3%. We have entered the third year of the trial and expect to complete participant visits this coming summer. The NHS will review early metrics from the first screening round of the study in 2024, and based on those results may commence the commercial implementation of the Galleri test in up to one million patients in England over two years.

In addition, we announced plans to initiate the Galleri-Medicare (REACH) study. This study is a first of its kind real-world study designed to evaluate the clinical impact of Galleri among 50,000 Medicare beneficiaries. The findings will add to our robust body of evidence evaluating the potential for MCEDs to change the future of cancer detection, particularly in diverse populations. Medicare will cover the costs of Galleri and related and routine items and services for study participants.  

Our clinical trial recruitment strategies are specifically designed to reach diverse and underrepresented populations. For example, we are partnering with medical centers and clinics in both rural and urban settings to recruit individuals with a representation consistent with the latest US census data in the PATHFINDER 2 study; the NHS-Galleri study includes enrollment centers in areas of high deprivation index and ethnicity mix in England; and the Galleri-Medicare real-world study is designed to include Medicare participants from underrepresented populations across race, ethnicity, socioeconomic status and underserved communities. 

We are building our pipeline 
Our proprietary targeted methylation platform, as well as our growing body of clinical and real-world data, provide us with unique insights into cancer biology that enable development of products beyond asymptomatic screening. We are developing our precision oncology portfolio and launched our research use only (RUO) technology solution, which couples our proprietary targeted methylation platform with customizable machine learning classifiers. We have partnered with a number of leading oncology therapeutics companies, and we shared our first lung adenocarcinoma data in collaboration with our partner AstraZeneca in December at the IASLC North America Conference On Lung Cancer. Some of our partnerships also include development of customized applications to support clinical studies and companion diagnostic development and commercialization.

In 2023, we published data from the SYMPLIFY study, demonstrating that our methylation platform was able to detect many cancer types and identify where the cancer signal origin was located in the body with high accuracy in a symptomatic patient population. Based on these findings, we are developing our diagnostic aid for cancer (DAC) test to accelerate diagnostic resolution for patients with non-specific signs and symptoms, but with a clinical suspicion of cancer. Through a blood test, DAC is designed to provide physicians with a powerful decision-making tool to aid diagnosis, achieve resolution more quickly, and avoid unnecessary workups. 

We are focused on MCED access
GRAIL is committed to broad and equitable access to our technology to help address healthcare disparities and improve clinical outcomes. By partnering with the healthcare community and its stakeholders, we are advancing the education of diverse and medically underserved communities about the importance of early cancer detection and supporting equitable access to our technology.

In addition to our clinical development program, GRAIL is pursuing innovative partnerships to improve cancer early detection rates for underserved populations, such as our partnerships with Ochsner Health, Whitman-Walker Institute and Cancer Support Community, and the U.S. Department of Veterans Affairs (VA) Veterans Health Administration and the Veterans Health Foundation. 

We are building a strong culture and team 
We have built a multi-disciplinary organization of leading scientists, engineers, clinicians and other talented professionals driven to improve outcomes for patients with cancer. We believe our mission, values, and leadership attributes all contribute to this vibrant and inclusive culture and serve as a powerful magnet for talent.

GRAIL was named on Fortune’s 2023 Change the World List, which recognizes companies addressing society’s biggest challenges and having a positive social impact, and Galleri was recognized with a 2023 Edison Award, one of the highest accolades a company can receive in the name of innovation. GRAIL was also voted a Best Place to Work by several organizations, including BuiltIn and Comparably.  

These achievements and accolades are only possible through the passion and commitment of our team. Pursuing scientific breakthroughs, scaling for growth and driving change across a dynamic environment requires that our team think big, bring an open mind, be courageous, solve problems together, and embrace change. Coupled with our mission, these core values provide the framework for how we work with each other, our commercial and research partners, healthcare providers, governments and others to drive the field forward and ultimately improve public health. I am grateful to our employees for their commitment to GRAIL and our mission every day.

Looking ahead
We anticipate that 2024 will be another transformative year as we expect to complete participant visits for the NHS-Galleri study, initiate the Galleri-Medicare study, further our innovative research, and continue to drive access to Galleri and advance our commercial and research partnerships. Looking beyond, we are focused on clear strategic goals including seeking Galleri FDA approval, pursuing CMS coverage and broad commercial reimbursement for Galleri, and launching additional products. 

On behalf of GRAIL’s leadership team and employees, we thank you for your continued support of our efforts to advance our mission to detect cancer early, when it can be cured.