ELIOS: A Multicenter, Molecular Profiling Study of Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer Treated with First-Line Osimertinib.
Summary
The prospective, multicenter ELIOS study characterized acquired resistance mechanisms to first-line osimertinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). By analyzing paired tumor biopsies taken pre-treatment and post-progression, the study identified frequent alterations including MET amplification, CDKN2A/CDKN2B and MTAP deletions, and the EGFR C797S mutation. Proteogenomic analysis also revealed high TROP2 expression, irrespective of genetic alterations. The findings highlight the heterogeneous nature of resistance and the complementary utility of tissue and liquid biopsies for alteration detection. This study emphasizes the need for therapeutic strategies targeting multiple resistance pathways.
Analysis
Clinique: This prospective Phase II study (NCT03239340) provides crucial data on resistance mechanisms to first-line osimertinib in EGFR-mutant NSCLC. The identification of multiple resistance pathways, such as MET amplification and the EGFR C797S mutation, suggests the need for combined or sequential therapeutic strategies to overcome this heterogeneity. The complementary role of tissue and liquid biopsies for post-progression molecular profiling is a significant point for clinical practice, potentially impacting treatment decisions in the short term (1-3 years). Biomol: The study utilized next-generation sequencing (NGS) on paired tissue biopsies to characterize acquired genetic alterations, validating known and identifying novel resistance mechanisms. The proteogenomic analysis represents a significant advancement, offering the first such characterization before and after osimertinib treatment, and revealing TACSTD2 (TROP2) as a potentially relevant proteomic marker, irrespective of genetic alterations. This opens avenues for new therapeutic targets and prognostic or predictive biomarkers.