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Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

Author

Listed:
  • Tereza Vaclova

    (Oncology R&D, AstraZeneca)

  • Ursula Grazini

    (Oncology R&D, AstraZeneca)

  • Lewis Ward

    (BioPharmaceutical R&D, AstraZeneca)

  • Daniel O’Neill

    (BioPharmaceutical R&D, AstraZeneca)

  • Aleksandra Markovets

    (Oncology R&D, AstraZeneca)

  • Xiangning Huang

    (Oncology R&D, AstraZeneca)

  • Juliann Chmielecki

    (Oncology R&D, AstraZeneca)

  • Ryan Hartmaier

    (Oncology R&D, AstraZeneca)

  • Kenneth S. Thress

    (Oncology R&D, AstraZeneca
    Oncology Business, AstraZeneca)

  • Paul D. Smith

    (Oncology R&D, AstraZeneca)

  • J. Carl Barrett

    (Oncology R&D, AstraZeneca)

  • Julian Downward

    (Francis Crick Institute)

  • Elza C. de Bruin

    (Oncology R&D, AstraZeneca)

Abstract

Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M‐positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.

Suggested Citation

  • Tereza Vaclova & Ursula Grazini & Lewis Ward & Daniel O’Neill & Aleksandra Markovets & Xiangning Huang & Juliann Chmielecki & Ryan Hartmaier & Kenneth S. Thress & Paul D. Smith & J. Carl Barrett & Jul, 2021. "Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22057-8
    DOI: 10.1038/s41467-021-22057-8
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    Cited by:

    1. Lavinia Tan & Chris Brown & Antony Mersiades & Chee Khoon Lee & Thomas John & Steven Kao & Genni Newnham & Kenneth O’Byrne & Sagun Parakh & Victoria Bray & Kevin Jasas & Sonia Yip & Stephen Q. Wong & , 2024. "A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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