ELIOS: A Multicenter, Molecular Profiling Study of Patients with EGFR -Mutant Advanced Non–Small Cell Lung Cancer Treated with First-Line Osimertinib

ELIOS (NCT03239340) prospectively compared tumor biopsies obtained pre-treatment and post-progression to characterize acquired resistance mechanisms to first-line osimertinib in epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). Of 154 patients enrolled, 52 patients had next-generation sequencing (NGS) results from paired tissue biopsies. The most common acquired alterations at progression were MET amplification (17%), deletion of CDKN2A/CDKN2B (15%) and MTAP (13%), and EGFR C797S (13%). Proteogenomic analysis (n = 32 at baseline and n = 18 post-progression) showed TROP2 was highly expressed at baseline and post-progression, irrespective of genetic alterations observed. In a separate analysis of patients with matched tissue and plasma samples post-progression (n = 51), 82% had potential resistance alterations by NGS, demonstrating the complementary roles of tissue and plasma NGS. These results highlight the challenges of obtaining tissue biopsies in patients with NSCLC progressing on targeted therapy, the potential for heterogeneous resistance, and the need for broad-acting treatment strategies. SIGNIFICANCE: ELIOS confirmed acquired resistance mechanisms to first-line osimertinib in a prospective, molecular profiling study of paired pre- and post-treatment tissue samples and provided the first proteogenomic characterization before/after osimertinib, identifying novel proteomic markers. ELIOS showed the potential for heterogeneous resistance, highlighting that strategies targeting multiple resistance pathways may be required.