Comprehensive epigenomic profiling of plasma for non-invasive detection of MET activation to uncover MET-associated biology in patients with <i>EGFR</i> -mutated advanced NSCLC and progression on osimertinib.

Abstract

8642 Background: Genomic overexpression or amplification of MET is an established bypass resistance mechanism in EGFR-mutated (EGFRm) NSCLC, observed in up to 34% of patients whose tumors progress on osimertinib. Savolitinib, an oral, highly selective MET TKI, demonstrates clinical activity in tumors classified as MET-high by tissue-based IHC or FISH. However, tissue at progression is often inaccessible or insufficient for repeated assessment, constraining dynamic characterization of MET pathway dependence and emerging resistance mechanisms. To overcome these limitations, we applied an epigenomic liquid biopsy platform to a subset of patients enrolled in the Phase II SAVANNAH trial that combined osimertinib and savolitinib after progression on 1L osimertinib (NCT03778229), where we evaluated the feasibility of capturing MET activity and additional resistance markers from plasma. Methods: Baseline samples from 40 patients enrolled in the SAVANNAH trial with progression on 1L osimertinib, were profiled using an epigenomic assay (Precede Biosciences, Boston MA) on 1mL of plasma. Tissue-based analysis from the SAVANNAH cohort scored 15/40 tumors as MET-high/+ (FISH 10+, IHC 3+ ≥90%+) and 25 samples as MET-low/- (FISH &lt; 10, IHC 3+ &lt; 90%). A plasma-based MET classifier integrating comprehensive epigenomic features was applied to these samples and its performance evaluated against tissue MET status. ctDNA fraction was independently estimated. Pathway analyses on genome-wide differential epigenomic activity were performed to define MET-associated biology and infer tumor gene expression from plasma. Results: The plasma-based MET classifier demonstrated strong agreement with tissue-based MET status (AUC 0.97; balanced accuracy 88%), with an estimated limit of quantification (LoQ) of ~0.8% ctDNA. MET+ samples displayed enrichment of epigenomic signatures consistent with MET-dependence, including MYC targets, metabolic signatures, and invasive and developmental programs. In contrast, MET-negative (MET-) samples were enriched for IFN-driven immune pathways and apoptotic priming. Gene expression models across multiple ADC targets applied to patient plasma samples from SAVANNAH also identified elevated EGFR and HER2 expression in select cases. Conclusions: Comprehensive epigenomic profiling of plasma demonstrated high concordance with tissue-based approaches, identifying MET pathway activation and additional putative resistance-associated targets, from 1 mL of plasma in EGFRm NSCLC patients. This provides an accessible and scalable blood-based test to increase identification of patients post-EGFR inhibitor treatment, who may benefit from MET-targeted therapy, resistance monitoring, and informing future combination or sequential MET-directed strategies.