Non-Invasive Molecular Testing for Osimertinib Acquired Resistance in T790M Positive Advanced Non-Small Cell Lung Cancer

Introduction: Data concerning the acquired resistance mechanisms to osimertinib in epidermal growth factor receptor (EGFR ) T790M -positive advanced non-small cell lung cancer (NSCLC) are limited, pwithin the Asian population. This study utilized Non-invasive Molecular Testing (NIMT) to characterize these resistance mechanisms and evaluate their clinical impact. Methods Advanced NSCLC patients with EGFR T790M positivity, treated with osimertinib after failure on first- or second-generation EGFR-TKIs at Ramathibodi Hospital (January 2016–December 2019), were prospectively enrolled. Plasma samples, collected at baseline and disease progression, were analyzed via Next-Generation Sequencing (NGS). Clinical outcomes were subsequently correlated with the molecular findings. Results Fifty patients were included in the analysis. A significant proportion (38%, n = 19) of patients exhibited more than one resistance mechanism. The most common resistance mechanism observed was T790M -loss (50%), followed by PIK3CA alteration (14%), EGFR C797S (10%), and MET alteration (6%). The median overall survival (OS) was 16.4 months, and the time to treatment failure (TTF) for osimertinib was 9.3 months. Patients experiencing T790M -loss trended toward a shorter TTF compared to those with T790M maintenance (6.0 vs 10.1 months, P = 0.21). Patients with T790M-maintained status combined with C797S exhibited shorter OS compared to those with T790M -maintained status without C797S (11.0 vs 15.2 months). Furthermore, patients with T790M -loss accompanied by other co-alterations demonstrated a shorter TTF than those with T790M -loss alone (4.1 vs 10.6 months, P = 0.07). A significant correlation was found between T790M -loss and the presence of clinical brain metastasis prior to osimertinib use (P = 0.04). Additionally, the development of brain progression after osimertinib was significantly correlated with the presence of a BRAF mutation (P = 0.01). Conclusion Acquired resistance to osimertinib is diverse. The presence of T790M -loss suggests a poorer TTF, and OS is compromised in patients developing EGFR C797S or T790M -loss with co-mutations. Molecular profiling at progression is crucial for guiding subsequent therapy.