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Introduction: 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)., Materials and Methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days 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., Results: 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 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity., Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR -mutated NSCLC at the expense of more toxicity., Competing Interests: Conflict of interest: R.G.P. Gijtenbeek has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: V. van der Noort has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: J.G.J.V. Aerts has received support for the present manuscript from Roche, Lilly and Amgen; consulting fees from MSD, BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca and BIOCAD, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from MSD, BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca and BIOCAD, outside the submitted work; and patents planned, issued or pending for an allogenic tumour cell lysate, Amphera, combination immunotherapy in cancer, and a biomarker for immunotherapy, unrelated to this submission. Conflict of interest: J.A. Staal-van den Brekel has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: E.F. Smit has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca and Bristol-Myers Squibb, outside the submitted work; and consulting fees from Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol-Myers Squibb, Merck KGaA, MSD Oncology, Takeda, Bayer, Novartis, Daiichi Sankyo and Seattle Genetics, outside the submitted work. Conflict of interest: F.H. Krouwels has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: F.A. Wilschut has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: T.J.N. Hiltermann has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts received from Roche, BMS and AstraZeneca, outside the submitted work; consulting fees received from Roche, BMS, AstraZeneca and MSD, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from BMS, outside the submitted work. Conflict of interest: W. Timens has received support for the present manuscript from Roche, Lilly and Amgen; and consulting fees received from Merck Sharp Dohme and Bristol-Myers-Squibb, outside the submitted work; and is a board member of the Dutch Society of Pathology and a member of the Council for Research and Innovation of the Federation of Medical Specialists. Conflict of interest: E. Schuuring has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from Abbott, Biocartis, Astrazeneca, Invitae/Archer, Bayer, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics and Boehringer Ingelheim, outside the submitted work; consulting fees from MSD/Merck, AstraZeneca, Roche, Novartis, Bayer, BMS, Lilly, Amgen, Illumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson&Johnson) and Astellas Pharma, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Bio-Rad, Seracare, Roche, Biocartis, Lilly, Agena Bioscience and Illumina, outside the submitted work; and support for attending meetings and/or travel from BioRad and Biocartis, outside the submitted work; and is an unpaid board member of the Dutch Society of Pathology, the European Society of Pathology and the European Liquid Biopsy Society. Conflict of interest: J.D.J. Janssen has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: M. Goosens has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: P.M. van den Berg has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: A.J. de Langen reports grants from BMS, MSD, Boehringer and AstraZeneca, and nonfinancial support from Merck Serono and Roche, outside the submitted work. Conflict of interest: J.A. Stigt has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: B.E.E.M. van den Borne has received support for the present manuscript from Roche, Lilly and Amgen. Conflict of interest: H.J.M. Groen has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from Roche and Boehringer Ingelheim, outside the submitted work; and consulting fees from Lilly, Novartis, Roche/Genentech and AstraZeneca, outside the submitted work. Conflict of interest: W.H. van Geffen has received support for the present manuscript from Roche, Lilly and Amgen; has unpaid roles for ERS and NVALT, outside the submitted work; and there have been trials run by his department funded by Roche and Amgen. Conflict of interest: A.J. van der Wekken has received support for the present manuscript from Roche, Lilly and Amgen; grants or contracts from AstraZeneca, Pfizer, Boehringer Ingelheim, Takeda and Roche, outside the submitted work; consulting fees from AstraZeneca, Novartis, Boehringer Ingelheim, Roche, Janssen, Pfizer, Lilly, Takeda and Merck, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Pfizer, outside the submitted work; and support for attending meetings and/or travel received from Lilly, outside the submitted work; and has a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid, for CPCT, outside the submitted work., (Copyright ©The authors 2022.)