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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\u201355), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating <jats:italic>EGFR<\/jats:italic> and <jats:italic>EGFR<\/jats:italic>-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 <jats:italic>EGFR<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41467-024-46008-1","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T13:02:34Z","timestamp":1709125354000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE"],"prefix":"10.1038","volume":"15","author":[{"given":"Lavinia","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2506-4871","authenticated-orcid":false,"given":"Chris","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony","family":"Mersiades","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chee Khoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3399-5342","authenticated-orcid":false,"given":"Thomas","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Kao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genni","family":"Newnham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"O\u2019Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagun","family":"Parakh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Bray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Jasas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Yip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen Q.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ftouni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerick","family":"Guinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushma","family":"Chandrashekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Pavlakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Stockler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8276-0374","authenticated-orcid":false,"given":"Sarah-Jane","family":"Dawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3059-5730","authenticated-orcid":false,"given":"Benjamin J.","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"46008_CR1","first-page":"2892","volume":"5","author":"A Midha","year":"2015","unstructured":"Midha, A., Dearden, S. & McCormack, R. 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Tan reports receiving speaker fees from Roche. C.K. Lee reports grants from AstraZeneca, Roche, Amgen, Merck KGA and honorarium from AstraZeneca, Amgen, GSK, Merck KGA, Novartis, Pfizer, Roche, and Takeda. He reports receiving travel fees from AstraZeneca. T. John reports receiving honorarium and is an advisory board member for BMS, AstraZeneca, Amgen, Roche, Pfizer, Takeda, Boehringer Ingelheim, MSD, Merck, Puma, Specialised Therapeutics, and Gilead. He reports receiving travel\/speaker fees from AstraZeneca and MSD. S. Kao serves on advisory boards for AstraZeneca, Pfizer, Roche, BMS, MSD, and Takeda. He reports receiving honorarium to institution for MSD, BMS, Roche, AstraZeneca, Pfizer, Boeringher Ingelheim and travel support from BMS, Roche, AstraZeneca, and Boeringher Ingelheim. K. O\u2019Byrne reports receiving honorarium from Merck Sharp & Dohme, BMS, Roche, Boehringer Ingelheim, AstraZeneca, Pfizer\/EMD Serano, Novartis, Janssen-Cilag, Yuhan, Tristar Technology Group, Takeda, Amgen, BeiGene. He has consulting\/advisory role for Merck Sharp & Dohme, Boehringer Ingelheim, Roche\/Genentech, Janssen-Cilag, Pfizer, AstraZeneca\/MedImmune, BMS, Novartis, Yuhan, Sanofi, Amgen, BeiGene. He has stock and other ownership interests with Carpe Vitae Pharmaceuticals, Replica Pharmaceuticals, DGC diagnostics and has four active patents (two published and two provisional). He also has speaking roles for Merck Sharp & Dohme, Boehringer Ingelheim, BMS, Roche, Janssen. S. Parakh reports receiving research funding from Bayer and Roche, honorarium from BMS and Roche. He is an advisory board member for AstraZeneca and MSD. S. Q. Wong reports receiving speaker fees from Roche. S. Clarke is an advisory board member for AstraZeneca and Beigene and has speaking roles for AstraZeneca. N. Pavlakis reports consulting or advisory role for Roche, Boehringer Ingelheim, AstraZeneca, Merck KGA, Merck Serono, Amgen, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, and BMS. M.R. Stockler reports receiving research funding from Astellas, Celgene, Bayer, Bionomics, Medivation, Sanofi, Pfizer, AstraZeneca, BMS, Roche, Amgen, Merck Sharp & Dohme, Tilray, and BeiGene. He has speaking roles for Astellas Pharma and Medivation\/Pfizer. SJ. Dawson has received research funding from Cancer Therapeutics CRC (CTx) and Genentech. She has been an advisory board member for AstraZeneca, Inivata and Adela. B. J. Solomon reports receiving honorarium and is an advisory board member for AstraZeneca, Pfizer, Novartis, Roche, Eli Lilly, Amgen, Merck, Bristol Myers Squibb, Takeda, Janssen, and BeiGene. No potential conflicts of interest were disclosed by the other authors.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1823"}}