Performance and safety of a multi-cancer early detection test: the PATHFINDER 2 study

Abstract

Early cancer detection improves survival; however, most cancer types do not have guideline-recommended screening. We previously reported the first PATHFINDER study that established feasibility of cancer screening with a blood-based multi-cancer early detection (MCED) test that predicts cancer signal origin (CSO) to guide diagnostic workup. The prospective, interventional PATHFINDER 2 study expands clinical evidence for the MCED test by evaluating co-primary endpoints of MCED performance metrics and safety in participants aged 50 years or older without clinical suspicion of cancer. Performance measures included cancer detection rate, positive and negative predictive values, episode sensitivity, specificity and CSO prediction accuracy. Safety was evaluated in terms of number and type of invasive procedures performed and adverse events due to diagnostic testing, after 12 months of follow-up. Endpoints were analyzed descriptively; no hypothesis testing was performed. Between December 2021 and July 2024, 35,878 participants were enrolled. Among 32,007 performance-analyzable participants, cancer detection rate was 0.54% (95% confidence interval (CI): 0.47−0.63%), positive predictive value was 60.3% (95% CI: 54.5−65.8%), negative predictive value was 99.2% (95% CI: 99.1−99.3%) and specificity was 99.64% (95% CI: 99.57−99.70%). Episode sensitivity was 39.3% (95% CI: 34.9−44.0%; all cancers) and 69.8% (95% CI: 62.8−76.0%; prespecified 12-cancer subgroup). Positive and negative likelihood ratios were 108.9 (95% CI: 87.6−135.2) and 0.61 (95% CI: 0.56−0.66), respectively, and the number needed to screen to detect one cancer was 185 (95% CI: 159−215). CSO prediction accuracy was 91.3%. Among 35,335 safety-analyzable participants, 213 (0.6%) had invasive procedure(s) after a positive MCED test; 90.5% were nonsurgical. No serious study-related adverse events were reported by the time of this analysis. These results provide insights into performance and safety of the MCED test in an intended-use population. Randomized trials and longer follow-up are needed to assess the clinical utility of MCED tests. ClinicalTrials.gov identifier: NCT05155605 . The interventional PATHFINDER 2 study provides insights on the safety and performance of a blood-based multi-cancer early detection test in an intended-use population, including more than 35,000 participants aged 50 years or older.