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Updated: Mar 7, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression
Helena A Yu1, Kwan Ho Tang2, Aleksandra A Markovets3
1Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
Purpose:
Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment.
Patients And Methods:
ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after 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 prespecified, 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 data was also assessed.
Results:
This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% 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.
Conclusions:
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. See related commentary by Gupta et al., p. 3718.
Insights
Understanding resistance mechanisms after first-line osimertinib treatment in EGFR-mutated non-small cell lung cancer (NSCLC) is crucial. The ORCHARD study identified common resistance alterations, informing potential combination therapies for improved patient outcomes.
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.
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