An exosome-based liquid biopsy predicts depth of response and survival outcomes to cetuximab and panitumumab in metastatic colorectal cancer: The EXONERATE Study.

PURPOSE EXONERATE (EXOsome and cell-free micro-RNAs of anti-EGFR ResistAnce) 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 AND METHODS Patients with newly diagnosed RAS-WT, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in 2-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 mCRC to predict PFS, OS, and ORR. RESULTS 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 vs. 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 mPFS (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 mPFS (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. CONCLUSION 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 vs. left approach.