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

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, Sarah Ftouni, Jerick Guinto, Sushma Chandrashekar, Stephen Clarke, Nick Pavlakis, Martin R. Stockler, Sarah-Jane Dawson () and Benjamin J. Solomon ()
Additional contact information
Lavinia Tan: Peter MacCallum Cancer Centre
Chris Brown: University of Sydney
Antony Mersiades: University of Sydney
Chee Khoon Lee: University of Sydney
Thomas John: Peter MacCallum Cancer Centre
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
Sarah Ftouni: Peter MacCallum Cancer Centre
Jerick Guinto: Peter MacCallum Cancer Centre
Sushma Chandrashekar: Peter MacCallum Cancer Centre
Stephen Clarke: Royal North Shore Hospital
Nick Pavlakis: Royal North Shore Hospital
Martin R. Stockler: University of Sydney
Sarah-Jane Dawson: Peter MacCallum Cancer Centre
Benjamin J. Solomon: Peter MacCallum Cancer Centre

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46008-1

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