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. (May 2019)

• Record Type: Journal Article
• Authors: Bordi, Paola; Del Re, Marzia; Minari, Roberta; Rofi, Eleonora; Buti, Sebastiano; Restante, Giuliana; Squadrilli, Anna; Crucitta, Stefania; Casartelli, Chiara; Gnetti, Letizia; Azzoni, Cinzia; Bottarelli, Lorena; Petrini, Iacopo; Cosenza, Agnese; Ferri, Leonarda; Rapacchi, Elena; Danesi, Romano; Tiseo, Marcello
• Is Part Of: Lung cancer. Volume 131(2019)
• Page Start: 78
• Page End: 85
• Publication Date: 2019-05
• Subjects: Osimertinib -- Liquid biopsy -- NSCLC -- EGFR mutation -- T790M; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2019.03.017
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Plasmatic levels of EGFR activating mutations at baseline affect prognosis. The plasmatic mutational load inversely correlates with outcome measures. Therascreen selects patients with high mutational load sample and worst outcome. T790M loss after progression is associated to EGFR-independent resistance mechanism. Abstract: Introduction: Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation 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 osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance. Materials and Methods: Forty patients with advanced NSCLC receiving osimertinib for 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 [< 2200 copies/mL or allele frequency (AF) < 6.1%] showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable 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.