From the beginning to resistance: Study of plasma monitoring and resistance mechanisms in a cohort of patients treated with osimertinib for advanced T790M-positive NSCLC

Abstract Introduction Analysis of circulating tumor DNA(ctDNA) for the identification of T790Mmutation in advanced EGFR -mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinibtreatment to correlate mutational levels with clinical outcome and to predict pattern of resistance. Materials and Methods Forty patients with advanced NSCLC receiving osimertinibfor T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed. Results Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA [ EGFR mutations in plasma ( shedders ) presented worse outcome than negative subjects ( non-shedders ). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation. Conclusions The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms.