Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Post-Progression...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Osimertinib is a standard first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
• Understanding resistance mechanisms post-osimertinib is vital for developing effective second-line therapies.
• The ORCHARD study investigated the tumor molecular profile following progression on first-line osimertinib.

Purpose of the Study:

• To explore mechanisms of resistance to first-line osimertinib in EGFR-mutated NSCLC.
• To characterize the histo-genomic landscape after osimertinib treatment.
• To assess agreement between tissue and plasma next-generation sequencing (NGS).

Main Methods:

• Phase II biomarker-directed study (ORCHARD, NCT03944772).
• Enrolled patients with EGFR-mutated NSCLC progressing on first-line osimertinib.
• Tumor molecular profiling via NGS of tissue and plasma samples.

Main Results:

• Comprehensive genomic data from 400 tissue and 191 plasma samples.
• TP53 and MDM2/4 alterations occurred in 85% of tumors and were mutually exclusive.
• Resistance alterations detected in 87% of samples, with multiple alterations in 46%.
• PI3K pathway, SOX2, and MYC alterations frequent in transformed tumors.
• Differential EGFR mutation patterns observed based on mutation type (L858R vs. exon 19 deletion).

Conclusions:

• Heterogeneous resistance mechanisms to first-line osimertinib are highlighted.
• Findings provide a rationale for combination therapies targeting resistance.
• Improved patient outcomes may be achieved through broad-acting combination treatments.