Evaluation of a novel blood-based lung nodule triage test in elevated-risk subjects.

10547 Background: In the National Lung Screening Trial (NLST), 4,354 (6%) of LDCT scans were positive with Lung RADS scores of 3 or 4A, and 162 lung cancers (LCs) were diagnosed within one year of the associated scan. Despite the elevated risk of malignancy, referral for immediate diagnostic (Dx) workup is not recommended; as a result, diagnosis is delayed by an average of 106 days compared with subjects assigned a Lung-RADS 4B or 4X score, who are referred for immediate Dx workup. This delay highlights the need for methods to further risk stratify these subjects and enable more timely evaluation. Tumor-associated extracellular vesicles and particles (EVPs) are highly abundant in blood and carry surface biomarkers from their tumor cell of origin, providing a readily measurable analyte class. We report performance of an EVP-based Lung Nodule Triage Test in detecting LC as a function of Lung RADS score in plasma samples from NLST subjects. Methods: The Triage Test (biomarkers and classifier) was locked following a training study. Here we evaluated the Triage Test in a blinded case-control study nested within the ACRIN Biomarker Arm of the NLST. The study included LC cases diagnosed within 24 months of blood draw (n = 51 cases; 99 samples), including longitudinal samples from 48 subjects. Controls were age-matched NLST subjects who had no LC detected before or within the trial follow up period with Lung RADS v1.1 scores of 1 or 2 (n = 60). Triage Test results were determined blinded to case-control status, with unblinding done by ECOG-ACRIN. A static threshold set to 90% specificity was applied to Triage Test scores. Results: Among the 99 samples with a diagnosis of LC within 24 months of blood draw, the Triage Test exhibited 34% sensitivity for detection of LC. The Triage Test exhibited 43% sensitivity in samples associated with LDCT-positive screen results not recommended for immediate Dx workup. The projected positive predictive value (PPV) for the Triage Test applied as a reflex test for individuals with Lung RADS 3 and 4A is 13.8% (95% CI: 5.7% - 30.5%, bootstrapping test sensitivity and specificity). Conclusions: The blood-based Lung Nodule Triage Test exhibits clinically meaningful performance for detection of LC among subjects with LDCT Lung RADS 3 and 4A scores. The data supports further evaluation of the Triage Test for reflex testing of indeterminant lung nodules. Lung RADS Score 1 2 3 4A 4B/X 3+4A Total NLST LDCT Arm # LDCT Screens 39,840 28,674 2,282 2,072 1,898 4,354 74,766 NLST LDCT Arm # LC Dx Within 12M of Screen 26 100 32 130 428 162 716 NLST LDCT Arm LC Prevalence 0.07% 0.3% 1.4% 6.3% 22.6% 3.7% 1.0% NLST LDCT Arm Avg. Days to Dx vs Lung RADS 4B/X 93 101 128 84 n/a 106 n/a Present Study # Cases 23 37 5 9 25 14 99 Present Study Triage Test Sensitivity 30% (7/23) 32% (12/37) 60% (3/5) 33% (3/9) 36% (9/25) 43% (6/14) 34% (34/99) Modeled Implications of Reflex Testing # True Positive Workups 8 32 19 43 154 69 246 Modeled Implications of Reflex Testing <jats:td colspan="1" rowspan="1"