Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.
Clin Cancer ResSep 1, 2026
Helena A Yu, Kwan Ho Tang, Aleksandra Markovets et al.
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In 30 seconds
The ORCHARD Phase II study investigated the genomic profiles of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) after progression on first-line osimertinib. The analysis of 400 tissue and 191 plasma samples revealed that resistance alterations were detected in 87% of samples, indicating significant heterogeneity in resistance mechanisms.
Key findings
- TP53 and MDM2/4 alterations were mutually exclusive and found in 86% of tumors.
- Resistance alterations were detected in 87% of samples, with multiple alterations in 46%.
- Alterations in the PI3K pathway, SOX2, and MYC were common in histologically transformed tumors.
- Differential patterns of co-occurring EGFR mutations were observed between L858R and exon 19 deletion tumors.
Why it matters
Understanding the genomic landscape of NSCLC after osimertinib progression can guide clinicians in selecting effective second-line therapies, potentially improving patient outcomes through tailored treatment strategies.