The prognostic value of longitudinal circulating tumor DNA profiling during osimertinib treatment

BACKGROUND: Serial profiling of circulating tumor DNA (ctDNA) could reflect dynamic molecular changes in response to treatment and potentially predict impending disease progression (PD). Herein, we investigated the molecular factors and dynamic changes in ctDNA that can serve as predictors of survival outcomes of patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) who received osimertinib therapy after progression from prior EGFR inhibitor regimen. METHODS: Capture-based targeted sequencing was performed on the baseline and longitudinal plasma samples collected from 72 and 57 patients, respectively, using a 168-gene panel. RESULTS: Analysis revealed that inferior overall survival (OS) was correlated with various baseline molecular features including high allelic fraction (AF) of EGFR sensitizing mutations (P=0.045), high maximum AF (maxAF, P=0.060), or harboring concurrent genomic alterations such as copy number amplification (CNA) in EGFR (P=0.026) or in other genes (P=0.026), and genes involved in the cell cycle (P=0.004) or TP53 signaling pathway (P=0.032). Moreover, ctDNA clearance at first follow-up after 6 weeks of osimertinib therapy was correlated with significantly longer progression-free survival (PFS) (P=0.022) and OS (P=0.009). Molecular PD, reflected by the emergence of new mutation or increased AF of existing mutations, was detected at an average lead time of 2.5 months prior to radiological PD. Patients with molecular PD were more likely to harbor CNA (P=0.035) and TP53 mutations (P=0.023). CONCLUSIONS: Molecular factors derived from serial ctDNA profiling can serve as predictive and prognostic markers, which could allow early detection of PD, preceding imaging modalities by 2.5 months.