GRAIL’s Galleri Test Cuts Stage 4 Cancer Diagnoses in Study Despite Missed Endpoint

Key Points

• GRAIL said its Galleri blood test showed it can shift cancer detection earlier and cut stage 4 diagnoses, with the NHS-Galleri study reporting more than a 20% reduction in stage 4 cancers in later screening rounds and a roughly fourfold increase in screen-detected cancers.
• Despite those results, the trial’s primary endpoint was not met: Galleri plus standard screening did not reduce the combined incidence of stage 3 and stage 4 cancers after three annual rounds, partly because many late-stage cancers were already present at the first screening.
• GRAIL also highlighted strong performance from PATHFINDER 2, including a 60.3% positive predictive value, 99.6% specificity and more than 90% cancer signal origin accuracy, while saying the test is intended to complement—not replace—existing cancer screenings.

GRAIL NASDAQ: GRAL said new data presented at the American Society of Clinical Oncology annual meeting showed its Galleri multi-cancer early detection blood test can identify more cancers through screening and reduce stage 4 diagnoses, though the company confirmed that a primary endpoint in its largest randomized trial was not met.

On an analyst call following the presentations, Chief Executive Officer Bob Ragusa said the company presented results from two large interventional studies: the NHS-Galleri trial in England and the PATHFINDER 2 study in North America. Dr. Josh Ofman, GRAIL’s President and CEO-Elect, said the results add to the company’s case for using Galleri alongside existing standard-of-care cancer screening.

“The NHS-Galleri study is the first time any MCED has demonstrated the ability to generate a stage shift in how cancers are detected,” Ofman said. He added that Galleri has now detected more than 150 distinct types of cancer across studies.

NHS-Galleri Trial Shows Stage 4 Reduction, But Misses Primary Endpoint

Dr. Harpal Kumar, GRAIL’s Chief Scientific Officer, said the NHS-Galleri trial enrolled more than 142,000 participants aged 50 to 77 with no recent cancer diagnosis or clinical suspicion of cancer. Participants were randomized to receive annual Galleri testing in addition to standard NHS screening or standard screening alone over three years.

The trial’s primary endpoint was a reduction in the combined incidence rate of stage 3 and stage 4 cancers after three annual screening rounds. Kumar said that endpoint was not met, a result the company had previously disclosed in February.

However, Kumar said the study showed several clinically meaningful secondary findings. In the incident screening rounds, which exclude the first “prevalent” round, stage 4 cancers were reduced by more than 20%. For the 12 pre-specified cancer types, Kumar said the reduction in stage 4 cancers was more than 22% in the second screening round and nearly 27% in the third.

The company also reported a 16% increase in stage 1 and stage 2 cancers for the 12 pre-specified cancer types after three screening rounds in the intervention arm compared with the control arm.

Kumar said the first screening round detected a large number of previously undiagnosed late-stage cancers, especially stage 3 cancers, which contributed to the trial missing its primary endpoint. He said the finding showed “just how much undiagnosed and uninvestigated stage 3 cancer is already prevalent in the population before any screening commences.”

Galleri Increased Screen-Detected Cancers

GRAIL said adding Galleri to NHS screening led to an approximate fourfold increase in screen-detected cancers. Kumar said more stage 1 and 2 cancers were detected by Galleri than all cancers detected by standard-of-care screening in the control arm.

The NHS-Galleri trial also showed a 21% reduction in cancers that needed to be detected through clinical presentation and a more than 25% decrease in cancers detected through emergency presentation, according to Kumar.

Across three screening rounds, 1,801 participants, or 0.91%, had a positive MCED result, and 937 were diagnosed with cancer, yielding a positive predictive value of 52%. Kumar said specificity was 99.55%, corresponding to a false positive rate of 0.45%, while the negative predictive value was almost 99%. Cancer signal origin accuracy was greater than 90%.

PATHFINDER 2 Data Reinforce Test Performance

GRAIL also presented full results from PATHFINDER 2, a study of nearly 36,000 participants aged 50 and older in North America with no clinical suspicion of cancer. The company had previously presented data from the first 25,000 participants.

Kumar said PATHFINDER 2 showed a positive predictive value of 60.3%, specificity of 99.6% and cancer signal origin accuracy above 90%. More than half of new cancers detected by Galleri were stage 1 or 2, and more than 70% had no U.S. Preventive Services Task Force grade A or B recommended screening, he said.

He said approximately 70% of new cancers detected by Galleri were found at stages 1 to 3, when treatment with curative intent is more often possible. GRAIL reported that screening detected six and a half times as many cancers when Galleri was used in addition to USPSTF grade A and B screening recommendations, and three times as many when used with grade A, B and C recommendations.

The company also highlighted safety results from PATHFINDER 2, saying 85% of diagnostic procedures were non-invasive. Five study-related adverse events were reported during diagnostic evaluation, all in participants with a cancer diagnosis, and none were serious.

Physicians Discuss Clinical Use

The call included comments from physicians who use or have studied Galleri. Dr. Mylynda Massart, an associate professor at the University of Pittsburgh and family medicine physician at UPMC, said she has incorporated multi-cancer early detection screening in a primary care precision medicine clinic, especially for patients with increased cancer risk due to age, family history, hereditary cancer variants or other exposures.

Dr. Nima Nabavizadeh, a radiation oncologist at Oregon Health & Science University, said his institution has worked up nearly 100 patients with signal-positive findings through GRAIL studies. He said the cancer signal origin result can help clinicians focus diagnostic workups, including in cases with subtle or indeterminate imaging findings.

Dr. Eric Su, an internal medicine physician in private practice in Los Angeles, said he has performed 1,277 Galleri screenings over three and a half years and has had six true positive results. Su said he discusses Galleri with many patients as an adjunct to, not a replacement for, established screening such as mammography and colonoscopy.

FDA, Reimbursement and Future Follow-Up

During the question-and-answer session, analysts asked about clinical utility, reimbursement and regulatory review. Ofman said the FDA package includes the first year of the NHS-Galleri trial and all of PATHFINDER 2, and that the agency is expected to focus on clinical validation and clinical performance. He said CMS and other payers are likely to be interested in stage-shift data.

GRAIL executives said they hope to continue following the NHS-Galleri population for at least another 12 months. Kumar said additional follow-up data could be available for analysis in the first or second quarter of next year, assuming agreement with the NHS.

Ofman said he does not expect a traditional mortality study to be conducted for a multi-cancer early detection test, though Kumar said GRAIL plans to explore mortality in NHS-Galleri through passive follow-up and a nested mortality analysis expected around 2028.

GRAIL executives emphasized that Galleri is intended to complement existing cancer screening programs. “The goal of all of this multi-cancer early detection is to find more cancers earlier when they’re more treatable and potentially curable,” Ofman said.

About GRAIL NASDAQ: GRAL

GRAIL, Inc NASDAQ: GRAL is a biotechnology company dedicated to the early detection of cancer through a multi-cancer blood test. Leveraging advances in next-generation sequencing, cell-free DNA (cfDNA) analysis and machine learning, GRAIL has developed the Galleri™ test, which aims to identify more than 50 types of cancer at their earliest stages. The company's platform analyzes methylation patterns in circulating tumor DNA to pinpoint tumor presence and tissue of origin, enabling physicians to pursue timely diagnostic follow-up.

Founded in 2016 as a spin-out from Illumina, GRAIL established its headquarters in Menlo Park, California, with additional research and operations centers in the United Kingdom.

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