A Deeper Dive Into Grail PATHFINDER Study Highlights Key Clinical Challenges; Unlikely to Be the Path to Broad Adoption and Insurance Coverage
GRAIL, a healthcare company focused on early cancer detection, has published the final results from its significant PATHFINDER study in The Lancet. The study involved over 6,600 adults over 50 without cancer symptoms and tested GRAIL’s multi-cancer early detection (MCED) blood test. The test identified cancers that lack recommended screening methods, enabling targeted diagnostics, and yielding results for most participants within three months.
On the positive front, when combined with standard screening, the MCED test more than doubled the number of cancer cases detected compared to standard screening alone. Approximately 48% of true positives were detected at early stages, potentially improving treatment outcomes. Patients found in early stages are most likely to benefit from improved clinical outcomes and positively impact the health economics surrounding the test. GRAIL highlighted the cancer patients detected in its release.
In the 6,621 participants, a cancer signal was detected in 92 individuals (1.4%). Out of the 92 with a cancer signal, 35 were diagnosed with cancer (true positives), while 57 did not have a cancer diagnosis (false positives). While the false positive rate relative to the overall number of study participants was low, physicians, and even more importantly health insurance providers, will likely be concerned with the diagnostic odyssey some of these patients may undergo. The study notes that one of the patients with a false positive even underwent a surgical procedure. Health economics are critical to driving insurance adoption. This test will be challenged by the low detection rate given it is a screening test, the low percentage of patients found with early stage cancers relative to the overall testing population which will drive the positive cost analysis, and the ancillary costs for screening patients who receive a false positive.
There are also the psychological implications for patients of receiving a false positive cancer diagnosis. Participant-reported outcomes regarding anxiety, distress, uncertainty, and satisfaction with the multi-cancer early detection (MCED) test were collected at various points in the study and the manuscript highlighted these results will be presented in a separate study.
Perhaps most importantly, 1.3% (86 out of 6529) were wrongly classified as false negatives, and 3.2% (208 out of 6529) did not have their cancer status assessed by the study’s end. When comparing the true positives to the false negatives, the Galleri test only detected 35 of 121 actual cancers of a sensitivity of 28.9%. Therefore, the test missed significantly more actual cancers (greater than 2 to 1) than it detected.
A good case study in how accuracy impacts test adoption and utilization is to look at Exact Sciences’ Cologuard test for colorectal cancer. The initial version of the test lacked high sensitivity and specificity. It wasn’t until Exact made significant enhancements and completed the large scale DeeP-C clinical study demonstrating exceptionally high sensitivity and specificity that broadscale clinical adoption by physicians, patients, and payers occurred. A similar phenomenon is likely to occur with multi-cancer detection tests for broad general screening.
Finally, insurance providers are likely to highlight that the population set tested in this study was very homogenous (91.7% were white) and not reflective of a real world testing population. Additionally the study participants were highly educated and had lower lifestyle risk factors such as smoking than the general population. There was also some enrichment for personal history of cancer and risk factors for cancer.
Additionally, the Nancy Gardner Sewell Medicare Multi-Cancer Early Detection (MCED) Screening Coverage Act has yet to be enacted by Congress but could be. This bipartisan legislation aims to provide Medicare coverage for emerging blood-based cancer screenings, potentially leading to earlier cancer detection. The bill seeks to make these screenings accessible to seniors once they are FDA-approved. The legislation received bipartisan support in the previous Congress, with over 400 organizations endorsing it, and could provide a path to Medicare coverage for multi-cancer early detection tests.
Overall, while the PATHFINDER study demonstrates multi-cancer detection tests can find additional cancers beyond traditional screening, it is likely further scientific enhancement of the technologies will be required before broadscale clinical adoption.