{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:20:19Z","timestamp":1792254019876,"version":"4.4.0"},"reference-count":21,"publisher":"European Respiratory Society (ERS)","issue":"4","license":[{"start":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018887","name":"Roche Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018887","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004312","name":"Eli Lilly and Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002429","name":"Amgen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002429","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["ERJ Open Res"],"accepted":{"date-parts":[[2022,7,5]]},"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Treatment-na\u00efve patients with an activating<jats:italic>EGFR<\/jats:italic>mutation, ECOG performance score of 0\u20133 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2\u201316 out of 21\u2005days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64\u2005months. Median PFS was 8.8\u2005months (95% CI 4.2\u201318.8) for CPE and 10.3\u2005months (95% CI 7.1\u201315.5; hazard ratio (HR) 0.78, 95% CI 0.32\u20131.91) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.32, 95% CI 0.10\u20131.01; p=0.02). ORR was 64% for CPE<jats:italic>versus<\/jats:italic>55% for erlotinib monotherapy. Median overall survival was 30.9\u2005months (95% CI 18.5\u201361.9 months) for CPE compared to 17.2\u2005months (95% CI 11.5\u201345.5 months) for erlotinib monotherapy (HR 0.66, 95% CI 0.27\u20131.65 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in<jats:italic>EGFR<\/jats:italic>-mutated NSCLC at the expense of more toxicity.<\/jats:p><\/jats:sec>","DOI":"10.1183\/23120541.00239-2022","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T15:35:29Z","timestamp":1660836929000},"page":"00239-2022","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI)<i>versus<\/i>intercalated TKI with chemotherapy for<i>EGFR<\/i>-mutated nonsmall cell lung cancer"],"prefix":"10.1183","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4202-5914","authenticated-orcid":false,"given":"Rolof G.P.","family":"Gijtenbeek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4910-4535","authenticated-orcid":false,"given":"Vincent","family":"van der Noort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G.J.V.","family":"Aerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeske A.","family":"Staal-van den Brekel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7329-6995","authenticated-orcid":false,"given":"Egbert F.","family":"Smit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans H.","family":"Krouwels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank A.","family":"Wilschut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0665-2160","authenticated-orcid":false,"given":"T. Jeroen N.","family":"Hiltermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-6363","authenticated-orcid":false,"given":"Wim","family":"Timens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed","family":"Schuuring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost D.J.","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"Goosens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"van den Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Joop","family":"de Langen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos A.","family":"Stigt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben E.E.M.","family":"van den Borne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry J.M.","family":"Groen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-0974","authenticated-orcid":false,"given":"Wouter H.","family":"van Geffen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthonie J.","family":"van der Wekken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2022,8,18]]},"reference":[{"key":"2024101711383362000_8.4.00239-2022.1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.08.001"},{"key":"2024101711383362000_8.4.00239-2022.2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.07.215"},{"key":"2024101711383362000_8.4.00239-2022.3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.840"},{"key":"2024101711383362000_8.4.00239-2022.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.05.1474"},{"key":"2024101711383362000_8.4.00239-2022.5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.66.9218"},{"key":"2024101711383362000_8.4.00239-2022.6","doi-asserted-by":"crossref","first-page":"viii495","DOI":"10.1093\/annonc\/mdy292.004","article-title":"Gefitinib with or without pemetrexed in nonsquamous (NS) non-small cell lung cancer (NSCLC) with EGFR mutation (mut): final overall survival (OS) results from a randomized phase II study","volume":"29","author":"Yang","year":"2018","journal-title":"Ann Oncol"},{"key":"2024101711383362000_8.4.00239-2022.7","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1200\/JCO.19.01154","article-title":"Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer","volume":"38","author":"Noronha","year":"2020","journal-title":"J Clin Oncol"},{"key":"2024101711383362000_8.4.00239-2022.8","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1200\/JCO.19.01488","article-title":"Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study","volume":"38","author":"Hosomi","year":"2020","journal-title":"J Clin Oncol"},{"key":"2024101711383362000_8.4.00239-2022.9","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.lungcan.2013.08.028","article-title":"Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib","volume":"82","author":"Tsai","year":"2013","journal-title":"Lung Cancer"},{"key":"2024101711383362000_8.4.00239-2022.10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2923"},{"key":"2024101711383362000_8.4.00239-2022.11","doi-asserted-by":"crossref","first-page":"931","DOI":"10.3892\/mmr.2014.2243","article-title":"Combined gefitinib and pemetrexed overcome the acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer","volume":"10","author":"Wu","year":"2014","journal-title":"Mol Med Rep"},{"key":"2024101711383362000_8.4.00239-2022.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.04.007"},{"key":"2024101711383362000_8.4.00239-2022.13","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2246"},{"key":"2024101711383362000_8.4.00239-2022.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0573-8"},{"key":"2024101711383362000_8.4.00239-2022.15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.lungcan.2016.06.018","article-title":"Quality of life, symptom status and physical performance in patients with advanced non-small cell lung cancer undergoing chemotherapy: an exploratory analysis of secondary data","volume":"99","author":"Shallwani","year":"2016","journal-title":"Lung Cancer"},{"key":"2024101711383362000_8.4.00239-2022.16","doi-asserted-by":"crossref","first-page":"3849","DOI":"10.1007\/s00520-020-05945-5","article-title":"Treatment goals and changes over time in older patients with non-curable cancer","volume":"29","author":"Stegmann","year":"2021","journal-title":"Support Care Cancer"},{"key":"2024101711383362000_8.4.00239-2022.17","doi-asserted-by":"crossref","first-page":"E647","DOI":"10.1016\/j.cllc.2020.05.019","article-title":"Nationwide real-world cohort study of first-line tyrosine kinase inhibitor treatment in epidermal growth factor receptor-mutated non-small-cell lung cancer","volume":"21","author":"Gijtenbeek","year":"2020","journal-title":"Clin Lung Cancer"},{"key":"2024101711383362000_8.4.00239-2022.18","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ejca.2021.02.019","article-title":"Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: an open-label, randomised phase 2 clinical trial","volume":"149","author":"Tanaka","year":"2021","journal-title":"Eur J Cancer"},{"key":"2024101711383362000_8.4.00239-2022.19","unstructured":"National Cancer Institute . Osimertinib with or without bevacizumab as initial treatment for patients with EGFR-mutant lung cancer. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04181060 Date last updated: 21 July 2022. Date last accessed: 6 September 2021."},{"key":"2024101711383362000_8.4.00239-2022.20","unstructured":"AstraZeneca . A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2). https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04035486 Date last updated: 13 July 2022. Date last accessed: 6 September 2021."},{"key":"2024101711383362000_8.4.00239-2022.21","doi-asserted-by":"crossref","first-page":"100271","DOI":"10.1016\/j.esmoop.2021.100271","article-title":"Osimertinib plus platinum\u2013pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced\/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study","volume":"6","author":"Planchard","year":"2021","journal-title":"ESMO Open"}],"updated-by":[{"DOI":"10.1183\/23120541.50239-2022","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000}}],"container-title":["ERJ Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/23120541.00239-2022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T05:20:37Z","timestamp":1740374437000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/23120541.00239-2022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,18]]},"references-count":21,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,10,17]]},"published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1183\/23120541.00239-2022"],"URL":"https:\/\/doi.org\/10.1183\/23120541.00239-2022","relation":{"correction":[{"id-type":"doi","id":"10.1183\/23120541.50239-2022","asserted-by":"object"}]},"ISSN":["2312-0541"],"issn-type":[{"value":"2312-0541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,18]]}}}