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ESMO Data Sharpens View of How Grail, Exact Sciences Multi-Cancer Early Detection Tests Perform

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PARIS – At the European Society for Medical Oncology Congress, updated analysis from the PATHFINDER study brought into greater focus the ability of Grail's Galleri test to detect early-stage cancers, while surveys provide insight into how oncologists are using the results and how patients feel about them.

Another retrospective analysis on Exact Sciences' multi-cancer early detection (MCED) test provided the first extensive view into its ability to detect a variety of cancer types as well as identify early- and late-stage disease.

On Sunday, Grail presented updated data from its PATHFINDER study, which is exploring the ability of its Galleri blood test to detect multiple cancers early. The firm launched the test, which analyzes cell-free DNA (cfDNA) for abnormalities in methylation patterns, as a laboratory-developed test in the US last year. The test is currently available for screening patients for incipient cancer if they are at elevated risk and as a complement to existing single cancer screening tests.

In the latest analysis, researchers used Galleri to analyze blood samples from 6,621 participants 50 years of age and older and followed all participants for one year, whether they had a positive result or not. The test detected a cancer signal in 1.4 percent, or 92, patients. Among those 92 patients, cancer was confirmed by follow-up screening in 35 patients, meaning the test correctly detected cancer in 0.5 percent of the entire cohort. The remaining 57 patients of the 92 who had a cancer signal by Galleri were deemed to have a false-positive result after follow-up screening.

After the initial return of results to patients in the PATHFINDER study, the researchers wanted to further refine the Galleri test. Using the banked patient samples, the researchers performed a second retrospective analysis on the samples. From the same 6,621 participants, the refined test identified 0.9 percent with a positive cancer signal, reducing the number of false positives from the first analysis. The test now has a positive predictive value of 43.1 percent and a specificity of 99.5 percent. It was able to predict the location of the tumor in 88 percent of positive cases.

In a 2021 analysis of the PATHFINDER study, researchers did not yet have the complete follow-up screening results from all 92 patients who had possible cancer. At the time, the data was missing secondary screening results from 29 patients who had a positive cancer signal by Galleri. The data presented at ESMO on Sunday included the full diagnostic workups from the 92 positive patients, providing a clearer picture of the rate of true and false positives among those identified with possible cancer by Galleri.

The false positives in the updated analysis may raise concerns about overdiagnosis, but Deb Schrag, chair of the department of medicine at Memorial Sloan Kettering Cancer Center, who presented the data, said the Galleri test caught a wider range of tumors, both common and rare. The test correctly identified the location of 36 different cancer types, with one of the 35 patients harboring both breast and endometrial tumors, Schrag said.

The test found either solid tumors or blood cancers in 24 participants in the high-risk patient cohort, defined by participants who had a history of smoking, documented genetic cancer predisposition, or personal history of cancer, and in 11 participants in the low-risk cohort. The test also identified 26 tumor types for which there is no standard screening method and 14 early-stage cancers.

"Some cancers are not that lethal, such as some prostate or thyroid cancers, but there are also cancers that are terribly lethal, like cholangiocarcinoma or pancreas cancer, that have no screening," Schrag said. These cancers identified by Galleri "are not all overdiagnosed cancers," she observed, noting that cholangiocarcinoma, uterine, and pancreas cancers "aren't normally diagnosed in the early stages, so that's powerful."

Federica Di Nicolantonio, professor in the department of oncology at the University of Turin, said in a discussion of the PATHFINDER results that the false positives could be due to several factors, such as cfDNA shedding from other conditions such as inflammatory disease or precancerous or benign lesions.

Physician, patient surveys

Schrag's team also explored how the test results were used by the physicians who ordered the MCED test, as well as whether the findings caused anxiety in patients. She noted that the physicians ordering Galleri were not given guidelines for which follow-up tests to perform for patients who had a positive result. In their analysis, they found it took a median of 79 days across all patients for diagnostic resolution. That time was shorter among patients who eventually had a cancer found, 59 days, and longer for patients who had false positives, 162 days.

"[Galleri] delivered the cancer signal of origin, but individual diagnostic workups depended on what was identified," Schrag said. "If there was a positive signal for head and neck cancer, for example, the physician would perhaps refer the patient to an [ear, nose, and throat] specialist for an exam. Many of the workups involved a CAT scan, or PET-CET scan of the torso, often including the chest, abdomen, and pelvis."

Schrag likened the additional workups patients needed after a positive Galleri result to patients today who must undergo another exam or ultrasound after an abnormal mammogram. Most participants who received a positive Galleri result (91 precent) underwent subsequent diagnostic imaging.

In the patient survey, the researchers measured the rates of anxiety, distress, uncertainty, and ultimate satisfaction with the results of the Galleri test. The survey showed that participants with a positive Galleri result had elevated anxiety, but anxiety levels returned nearly to baseline levels by the end of the study period. Patients also reported a high rate of satisfaction irrespective of their result.

Exact's MCED test

At the meeting, researchers also reported retrospective analysis on the MCED test being developed by Exact Sciences. The liquid biopsy test came to Exact through its 2020 acquisition of Thrive Earlier Detection.

In the ESMO study, researchers used Exact's test to analyze 600 cancer samples from 12 organ types and 1,920 non-cancer samples. The study included cancerous and normal samples, with the cancerous samples from patients with tumors in the breast, bladder, colon, esophageal, kidney, liver, lung, ovarian, pancreatic, prostate, stomach, and uterus, as well as from multiple myelomas, myelodysplastic syndromes, and non-Hodgkin's lymphomas.

Researchers reported that by factoring in combined aneuploidy, DNA methylation, and protein markers, the test detected cancer across all 12 organ types and across cancer stages with a mean overall sensitivity of 52.6 percent and a mean specificity of 98.7 percent.

Across different cancer stages, the specificity of the test varied. For early stage I/II tumors, the sensitivity was 36 percent, while the test had higher sensitivity for detecting later-stage tumors: 59.9 percent for stage III tumors and 87.7 percent for stage IV tumors. The test sensitivity also varied depending on the tumor's location, with the lowest sensitivity for detecting prostate and kidney cancers and highest for identifying liver and ovarian cancers.

Exact Sciences said in a statement that a larger retrospective analysis study is underway to validate these results. The firm then plans to begin recruiting patients for a registrational clinical trial of the test, called Study Of All comeRs (SOAR), in 2023.

There are several other MCED tests currently in development including assays from Freenome, Guardant Health, and Delfi Diagnostics. The National Cancer Institute is also seeking partners for a randomized study of a MCED.

Grail, meanwhile, is also further testing the accuracy of Galleri in a larger study, PATHFINDER 2, in which it will enroll and screen 20,000 patients with its multi-cancer early detection test, making it around three times bigger than the first PATHFINDER study.

"[PATHFINDER] shows that it is indeed feasible to detect cancers early using a blood test," Schrag said. "It's important to conduct clinical utility studies to evaluate whether MCED testing reduces mortality, which is the primary goal of all cancer screening."