Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Post-Progression on First-Line Osimertinib: Phase II ORCHARD Study.

Abstract

Osimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFR-mutated NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile post-progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a pre-specified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS was also assessed. The study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histo-genomic landscape post-first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 85% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes.