Plasma epigenomic profiling for identification of mechanisms of sensitivity, primary and acquired resistance to tepotinib in METex14 skipping metastatic NSCLC.

Abstract

8637 Background: MET exon 14 skipping mutations (METex14) are an actionable biomarker in a subset (3-4%) of advanced/metastatic NSCLC patients, with an approved oral and highly selective MET TKI, tepotinib. However, heterogenous clinical responses in patients warrant additional biomarkers of response and resistance. We applied Precede’s epigenomic liquid biopsy platform to explore the feasibility of identifying transcriptional programs associated with sensitivity and resistance to tepotinib in patients with METex14 NSCLC. Methods: A total of 144 baseline, on-treatment (OT), and end-of-treatment (EOT) samples from patients with METex14 NSCLC from the VISION study (NCT02864992) were profiled using Precede’s assay using 1mL of plasma. ctDNA fraction was independently estimated. Genome-wide differential epigenomic activity and pathway analyses compared PFS-stratified responders (top tertile PFS) vs. non-responders at baseline (bottom tertile PFS), and paired baseline vs. EOT samples to identify acquired resistance programs. SCLC/neuroendocrine transformation was assessed in all samples using an independent Precede lineage classifier. Plasma-inferred gene expression models, based on Precede’s proprietary algorithms identified additional therapeutic targets. Results: At baseline, responders showed higher epigenomic activity in pathways underlying addiction to METex14 signaling, including the FAK-integrin axis, ECM remodeling and EMT/invasion. Non-responders displayed increased translational/intrinsic proliferative programs, altered metabolic fitness, and inflammatory/immune signaling, implicating these programs in intrinsic resistance to tepotinib. These METex14 signaling-associated pathway scores stratified clinical outcomes, highlighting their potential in patient selection. Paired analyses revealed EOT samples had increased activity of regulators of lineage plasticity and neuroendocrine differentiation, relative to baseline. Correspondingly, SCLC scores were elevated in OT and EOT samples, with a subset of baseline samples already harboring neuroendocrine features. Epigenomic activity of GD2 synthase ( B4GALNT1 ) significantly increased with treatment, underscoring a potential rationale for combination therapies using anti-GD2 ADCs. Conclusions: Precede’s comprehensive epigenomic liquid biopsy platform resolved METex14 skipping NSCLC biology associated with response and identified programs associated with intrinsic and acquired resistance to tepotinib, including emergence of neuroendocrine differentiation and induction of GD2 synthase. These findings support the use of plasma-based epigenomic profiling to inform therapy selection for patients at baseline and progression and non-invasively monitor resistance mechanisms in METex14 NSCLC.