Comparison of Resistance Spectra after First and Second Line Osimertinib Treatment Detected by Liquid Biopsy

Area of Science:

• Oncology
• Genomics
• Medical Diagnostics

Background:

• First, second, and third-generation EGFR tyrosine kinase inhibitors (TKIs) are approved for EGFR-mutated metastatic non-small cell lung cancer (NSCLC).
• While effective, resistance to TKIs, particularly after one year for first and second-generation inhibitors, is inevitable.
• Third-generation TKI osimertinib shows improved progression-free survival but exhibits a more diverse spectrum of resistance alterations.

Purpose of the Study:

• To evaluate the utility of liquid biopsy using hybrid capture-based next-generation sequencing (NGS) for comprehensive molecular profiling in metastatic NSCLC patients experiencing disease progression on osimertinib treatment.
• To identify diverse TKI resistance mechanisms, including single and multiple alterations across various pathways, copy number changes, and rare fusions.
• To demonstrate the added value of NGS in liquid biopsies for detecting polyclonal resistance development at the DNA level.

Main Methods:

• Real-world data from 56 metastatic NSCLC patients treated with osimertinib were analyzed.
• Liquid biopsies were performed at the time of disease progression.
• Hybrid capture (HC)-based next-generation sequencing (NGS) was employed for comprehensive genomic profiling.

Main Results:

• The study identified various single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number alterations, and rare fusions (RET, ALK, FGFR3, BRAF).
• HC-based NGS successfully revealed polyclonal resistance development, exemplified by concurrent EGFR C797S and PIK3CA mutations.
• Liquid biopsy analysis demonstrated concordance with previous findings comparing it to solid tumor biopsies.

Conclusions:

• Liquid biopsy coupled with HC-based NGS is a valuable tool for comprehensive molecular characterization of resistance mechanisms in EGFR-mutated NSCLC patients progressing on osimertinib.
• This approach facilitates the identification of therapeutically targetable alterations, guiding subsequent treatment decisions.
• Detecting polyclonal resistance is crucial for understanding disease evolution and optimizing therapeutic strategies in NSCLC.