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A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE

Author

Listed:
  • Lavinia Tan

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Chris Brown

    (University of Sydney)

  • Antony Mersiades

    (University of Sydney)

  • Chee Khoon Lee

    (University of Sydney
    St George Hospital)

  • Thomas John

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Steven Kao

    (Chris O’Brien Lifehouse)

  • Genni Newnham

    (St Vincent’s Hospital)

  • Kenneth O’Byrne

    (Princess Alexandra Hospital)

  • Sagun Parakh

    (Austin Hospital, Olivia Newton John Cancer and Wellness and Research Centre)

  • Victoria Bray

    (Liverpool Hospital)

  • Kevin Jasas

    (Sir Charles Gairdner Hospital)

  • Sonia Yip

    (University of Sydney)

  • Stephen Q. Wong

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

  • Sarah Ftouni

    (Peter MacCallum Cancer Centre)

  • Jerick Guinto

    (Peter MacCallum Cancer Centre)

  • Sushma Chandrashekar

    (Peter MacCallum Cancer Centre)

  • Stephen Clarke

    (Royal North Shore Hospital
    University of Sydney)

  • Nick Pavlakis

    (Royal North Shore Hospital
    University of Sydney)

  • Martin R. Stockler

    (University of Sydney)

  • Sarah-Jane Dawson

    (Peter MacCallum Cancer Centre
    The University of Melbourne
    The University of Melbourne)

  • Benjamin J. Solomon

    (Peter MacCallum Cancer Centre
    The University of Melbourne)

Abstract

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5–55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46008-1
    DOI: 10.1038/s41467-024-46008-1
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    References listed on IDEAS

    as
    1. Jacob J. Chabon & Andrew D. Simmons & Alexander F. Lovejoy & Mohammad S. Esfahani & Aaron M. Newman & Henry J. Haringsma & David M. Kurtz & Henning Stehr & Florian Scherer & Chris A. Karlovich & Thoma, 2016. "Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients," Nature Communications, Nature, vol. 7(1), pages 1-15, September.
    2. 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.
    3. Jacob J. Chabon & Andrew D. Simmons & Alexander F. Lovejoy & Mohammad S. Esfahani & Aaron M. Newman & Henry J. Haringsma & David M. Kurtz & Henning Stehr & Florian Scherer & Chris A. Karlovich & Thoma, 2016. "Correction: Corrigendum: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients," Nature Communications, Nature, vol. 7(1), pages 1-1, December.
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