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Cancer screening has transformed outcomes for several cancers, but the vast majority of cancer deaths still occur in patients who have cancers without recommended screening tests. Multi-cancer early detection (MCED) tests can help address that gap. Rather than screening for one cancer at a time, the Galleri ® MCED test looks for a shared cancer signal in blood and, when a signal is found, predicts the Cancer Signal Origin (CSO) with high accuracy to help guide follow-up.
To develop and launch Galleri, GRAIL has built what we believe is the largest clinical program in genomic medicine to-date, enrolling more than 380,000 participants across nine clinical trials. Many of these studies have published results ( Liu 2020 , Klein 2021 , Jamshidi 2022 , Nicholson 2023 , Schrag 2023 ), including clinical validation across our CCGA3 case-control study and the PATHFINDER interventional trial in an intended-use screening population ( Klein 2021 , Schrag 2023 , Ofman 2025 ).
As we approach completing submission of our Premarket Approval (PMA) package to the FDA in the first half of 2026, attention is turning to readouts from our two registrational trials: PATHFINDER 2, the largest U.S.-based interventional MCED study, and NHS-Galleri, the first and only population-scale randomized controlled trial of an MCED. With initial results from PATHFINDER 2 expected at the European Society for Medical Oncology (ESMO) Congress in October 2025 ( GRAIL 2025 [1] ), the readout will be an important milestone for understanding how MCED can be implemented in everyday clinical practice, as well as the path to population scale adoption.
What PATHFINDER 2 is Designed to Do
PATHFINDER 2 is a prospective, single-arm, return-of-results trial designed to evaluate Galleri’s performance, safety, and implementation in an intended-use population. A clinical utility measure — the cancer detection rate in the population when added to SOC screening tests — will also be assessed. The trial enrolled 35,878 adults aged 50 and older across healthcare systems in the U.S. and Canada who were eligible for routine, guideline-recommended screening and had no signs or symptoms raising clinical suspicion of cancer.
The cohort was intentionally diverse by race, ethnicity, age (including those over 80), and prior cancer history, to reflect day-to-day clinical practice and help minimize the “healthy volunteer bias” often seen in screening trials. Participants provided a single blood draw at enrollment and were followed for 12 months to determine cancer status (i.e., presence or absence of cancer).
The primary objectives are two-fold: to evaluate the safety of Galleri in terms of the blood draw and diagnostic testing triggered by the test result, and to evaluate performance of the Galleri test in individuals eligible for cancer screening.
Diagnostic Testing and Safety
Because PATHFINDER 2 returns results to participants and their providers, it captures diagnostic pathways in real time. For those with a “Cancer Signal Detected” result, we track what follow-up tests were ordered, how invasive they were, and how quickly a diagnostic resolution (whether cancer was present or not) was reached. Building on the first PATHFINDER trial, where most evaluations began with imaging and invasive procedures were generally reserved for cases with clear clinical pathways, PATHFINDER 2 also focuses on safety, with the goal of minimizing unnecessary testing, avoiding harm where possible, and helping people with a positive result reach diagnostic resolution efficiently.
For participants with a “No Cancer Signal Detected” result, our communications to participants reinforce a critical message: continue all routine screenings for cancers like breast, cervical, colorectal, lung (for those at high risk), and prostate. MCED is designed to complement, not replace, guideline-recommended screening.
Key Performance and Clinical Utility Measures and Why They Matter
PATHFINDER 2 will also report a standard set of performance measures, covered in more detail in a separate post . Two measures are worth calling out here, both of which are critical measures of a multi-cancer test’s performance:
• Positive Predictive Value (PPV): Among those with a positive test result, how often cancer is truly present, and
• Cancer Detection Rate (CDR): How often the test finds cancer in a screened population.
Both are crucial for evaluating MCED test performance. On an individual-level, a higher PPV – partially driven by maintaining a very low false positive rate of 0.5% as well as the aggregate prevalence of cancers – means fewer unnecessary procedures and higher confidence in a positive test result. On a population-level, a higher CDR means many more screen-detected cancers are found before symptoms arise in the patient population.
We believe that measures such as PPV and CDR are the most informative for understanding an MCED test’s performance, and that these must be measured in an intended use population trial like PATHFINDER 2 ( Ofman 2025 ).
What PATHFINDER 2 Is Not Designed to Do
Equally important is what this trial is not designed to address. PATHFINDER 2 does not measure whether adding MCED to usual care reduces late-stage cancer incidence, a clinical utility endpoint. Those types of endpoints require large randomized controlled trials with multi-year testing and follow-up ( Kumar 2024 , Neal 2022 ). The NHS-Galleri trial in England was designed specifically for that purpose and results are expected in mid-2026.
Building on Prior Evidence
Although no single study can answer every question, the PATHFINDER 2 trial represents a pivotal step. It builds on our robust clinical validation studies: the case-control CCGA study ( Klein 2021 ) and the interventional intended use PATHFINDER trial ( Schrag 2023 ). The first PATHFINDER trial showed that adding MCED to recommended screening more than doubled the number of cancers detected, that most CSO-directed follow-up evaluations led directly to diagnostic resolution, and that invasive procedures were largely concentrated in those who truly had cancer. That trial also reported a high PPV of 43.1%, underscoring the urgency of that directed workup ( Schrag 2023 ). PATHFINDER 2 builds on these results in a much larger, more diverse U.S. cohort. And, more recently, the PATHFINDER 2 and NHS-Galleri trials reported encouraging top-line results, including PPVs that are substantially higher than observed in prior clinical studies ( GRAIL 2025 [2] , GRAIL 2025 [3] ).
Looking Ahead
In the bigger picture, PATHFINDER 2 is expected to clarify how MCED can be implemented in routine practice, as well as the additional cancers detected when added to SOC screening (cancer detection rate). NHS-Galleri is intended to inform what population-scale use could mean for reducing late-stage diagnoses and improving longer-term outcomes.
Together, these trials are providing an expanded evidence base for responsible, large-scale adoption of MCED. For patients, providers, and health systems, the PATHFINDER 2 readout represents a meaningful step towards population-scale MCED implementation, and ultimately a paradigm shift in cancer screening.
References
GRAIL, Inc [3] (2025, September 25). GRAIL to Present New Galleri ® Data From More Than 32,000 Participants Across the PATHFINDER 2, SYMPLIFY and REFLECTION Studies at ESMO Congress 2025 and EDCC [press release]. https://grail.com/wp-content/uploads/2024/01/Mission_wall_obrien-1-6.jpgwp-content/uploads/2024/01/Mission_wall_obrien-1-5.jpgwp-content/uploads/2022/11/TIME_Best_Inventions_2022-4.jpgpress-releases/grail-to-present-new-galleri-data-from-more-than-32000-participants-across-the-pathfinder-2-symplify-and-reflection-studies-at-esmo-congress-2025-and-edcc/
GRAIL, Inc. [2] (2025, May 13). GRAIL Reports First Quarter 2025 Financial Results [press release]. https://grail.com/wp-content/uploads/2024/01/Mission_wall_obrien-1-6.jpgwp-content/uploads/2024/01/Mission_wall_obrien-1-5.jpgwp-content/uploads/2022/11/TIME_Best_Inventions_2022-4.jpgpress-releases/grail-reports-first-quarter-2025-financial-results/
GRAIL, Inc. [3] (2025, June 18). GRAIL Announces Positive Top-Line Results From The Galleri ® PATHFINDER 2 Registrational Study [Press release]. https://grail.com/wp-content/uploads/2024/01/Mission_wall_obrien-1-6.jpgwp-content/uploads/2024/01/Mission_wall_obrien-1-5.jpgwp-content/uploads/2022/11/TIME_Best_Inventions_2022-4.jpgpress-releases/grail-announces-positive-top-line-results-from-the-galleri%e2%93%a1-pathfinder-2-registrational-study/
Jamshidi A, Liu MC, Klein EA, et al. Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell. 2022;40(12):1537-1549.e12.
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.
Liu MC, Oxnard GR, Klein EA, et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-759.
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 (Basel). 2022;14(19):4818.
Nicholson BD, Oke J, Virdee PS, et al. Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study. JAMA Onc. 2023;24(7):733-743.
Ofman J, Hall MP, Clarke-Dur C. Not all MCED tests are created equal: the realities of test development and validation. July 31, 2025. Available at grail.com/ . Accessed September 10, 2025.
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.
For further details about Galleri test performance, visit grail.com/ and galleri.com .