Journal Article

Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies

Buti, S., Ampollini, L., Verzè, M., La Monica, S., Lagrasta, C. A. M., Gasparro, D., Perrone, F., Leonetti, A., Bordi, P., Bottarelli, L., Silini, E. M., Pluchino, M., Nizzoli, R., Cosenza, A., Ferri, L., Alfieri, R., Tiseo, M., Minari, R., Gnetti, L., Majori, M., Azzoni, C., Mazzaschi, G., De Filippo, M.

2024

Overview

Background Resistance to osimertinib in advanced EGFR- mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. Methods This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR- mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. Results Sixty-five advanced EGFR -mutated NSCLC patients treated with osimertinib in first- ( n  = 56) or in second-line ( n  = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification ( n  = 8), EGFR C797S ( n  = 3), and SCLC transformation ( n  = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. Conclusions Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/395 / 631/67/69 / 692/4017 / 692/4028/67/1612/1350 / Acrylamides / Aniline Compounds - therapeutic use / Biomedical and Life Sciences / Biomedicine / Biopsy / Cancer Research / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Drug Resistance / Drug Resistance, Neoplasm - genetics / Epidemiology / Epidermal growth factor receptors / ErbB Receptors - genetics / Genotype / Genotyping / Humans / Indoles / Liquid Biopsy / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Molecular Medicine / Mutation / Next-generation sequencing / Non-small cell lung carcinoma / Oncology / Plasma / Prospective Studies / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Pyrimidines / Sequence analysis / Small cell lung carcinoma / Targeted cancer therapy