An Exosome-Based Liquid Biopsy Predicts Depth of Response and Survival Outcomes to Cetuximab and Panitumumab in Metastatic Colorectal Cancer: The EXONERATE Study.

Abstract

The EXOsome and cell-free miRNAs of anti-EGFR ResistAnce (EXONERATE) study was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC). Patients with newly diagnosed RAS wild-type, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in two nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRCs to predict PFS, OS, and ORR. Genome-wide small RNA sequencing identified 12 cell-free and 14 exosomal candidates that were differentially expressed in both plasma and tumor tissue of good versus poor responders (based on PFS <12 months). The 8 and 9 best performing candidates, respectively, were used to generate the EXONERATE assay. In left-sided mCRC, 65% were EXONERATE-high, correlating with shorter median PFS (9.5 vs. 18.5 months; P < 0.001). In the independent right-sided mCRC cohort, 80.8% were EXONERATE-high and experienced a similarly shorter median PFS (8.6 vs. 41.2 months; P = 0.0004). In the right-sided group, EXONERATE predicted PFS ≥12 months with 100% sensitivity. A linear relationship existed between EXONERATE values and response depth. Multivariate analysis revealed that EXONERATE predicts PFS and OS independently of tumor sidedness. The EXONERATE assay robustly predicted PFS and OS outcomes in patients with mCRC, both right- and left-sided, before they received either panitumumab or cetuximab. It stratified PFS, OS, and ORR better than a right versus left approach.