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Rethinking Molecular Profiling after First-line Osimertinib

Komal Gupta1,2, Daniel S W Tan1, Regina Hoo3

  • 1National Cancer Centre Singapore, Singapore.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 10, 2026
PubMed

Insights

The ORCHARD study reveals complex resistance mechanisms after first-line osimertinib treatment. Histo-genomic analysis found resistance alterations in 87% of patients, with 46% showing polyclonal resistance, impacting future treatment strategies.

Area of Science:

  • Oncology
  • Genomics
  • Pharmacology

Background:

  • First-line osimertinib is a standard treatment for EGFR-mutated non-small cell lung cancer.
  • Understanding resistance mechanisms is crucial for optimizing subsequent therapies.
  • The ORCHARD study provides the largest histo-genomic characterization of osimertinib resistance to date.

Purpose of the Study:

  • To comprehensively characterize resistance alterations following first-line osimertinib treatment.
  • To investigate the prevalence of polyclonal resistance mechanisms.
  • To inform the development of next-generation treatment strategies in the post-EGFR TKI setting.

Main Methods:

  • Dual-modality sequencing of both tissue and plasma samples.
  • Histo-genomic analysis of patient samples from the ORCHARD study.

Main Results:

  • Resistance alterations were detected in 87% of patients.
  • Polyclonal resistance mechanisms were identified in 46% of cases.
  • The findings highlight the complex biological landscape of post-osimertinib resistance.

Conclusions:

  • Osimertinib resistance is complex and frequently involves polyclonal mechanisms.
  • These findings raise important questions regarding the efficacy of targeted versus broadly acting regimens after EGFR TKI failure.
  • Further research is needed to guide optimal treatment sequencing.

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