Plasma-Based Genomic Features Influencing Outcomes of T790M-Positive Non-Small Cell Lung Cancer Receiving Osimertinib

Circulating tumor DNA (ctDNA) provides a noninvasive method to clarify patients' genomic alterations. This study evaluated plasma-derived ctDNA before second-line osimertinib administration to explore the relationships between genomic alterations and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC).

We included 64 advanced NSCLC patients with EGFR T790M receiving second-line osimertinib. Targeted DNA sequencing was conducted on plasma samples, and both clinical and genomic characteristics were assessed for the correlation with clinical outcomes.

Female patients showed longer progression-free survival (PFS) than male patients. Smokers exhibited shorter PFS and overall survival (OS) than nonsmokers. EGFR exon 19 deletion (E19Del) tended to have improved PFS compared with L858R. Plasma T790M abundance was not associated with the response to osimertinib, PFS, or OS. Patients with TP53 mutations experienced significantly worse PFS than wild-type ones. A significant PFS reduction was observed in patients with a blood tumor mutational burden (bTMB) ≥ 8, compared to those with a bTMB ⟨ 8 mut./Mb. The EGFR driver mutation type (E19Del versus L858R) and TP53 mutation status were independent factors influencing PFS by multivariate survival analysis. Furthermore, the combination of EGFR driver type and TP53 mutation status improved the predictive performance for clinical outcomes, including objective response rate (ORR) and PFS, but not OS.

This study identified potential molecular features via ctDNA sequencing that were correlated to clinical outcomes in EGFR T790M-positive advanced NSCLC treated with second-line osimertinib.