Background: Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression., Methods: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540., Findings: Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests MÖ reports consulting fees, support for attending meetings, and participation in an advisory board from Regeneron Pharmaceuticals. AS reports support for attending meeting from Regeneron Pharmaceuticals. MS reports research grants from Regeneron Pharmaceuticals, Bristol Myers Squibb, MSD, Roche, Merck Serono, AstraZeneca, Eli Lilly, Astellas, Amgen, BeiGene, Bayer, Eisai, Pfizer, GSK, AbbVie, Bioven, Novartis, Clovis, Daichii Sankyo, PharmaMar, Tesaro, and FivePrime. IC reports personal fees (paid to institution) from Pfizer, MSD Oncology, Roche, Novartis–Ipsen, Eli Lilly, Bristol Myers Squibb, SERVIER, Abdi Ibrahim, Nobelpharma, AbbVie, Teva, and Janssen Oncology; and speakers' bureau fees (paid to institution) from Novartis, Roche, Bristol Myers Squibb, Pfizer, and Abdi Ibrahim, all outside the submitted work. GFH reports research grants from EliLily, Regeneron Pharmaceuticals, MSD, AB Science, Astellas, Tessa Therapeutics, Roche, Arcus Bioscience, AstraZeneca, Pfizer, and Janssen Research & Development; payment or honoraria from MSD, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, and Pfizer; support for attending meetings or travel from Ipsen, AstraZeneca, Bristol Myers Squibb, MSD, and Regeneron Pharmaceuticals; DSMB or advisory board fees from MSD, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, and Pfizer; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Pfizer, Novartis, Janssen Pharmaceuticals, Taiho, and EliLily. MCG reports personal financial interests in the form of consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and participation on a DSMB or advisory board from AstraZeneca, MSD, BMS, Boehringer Ingelheim Italia, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regerenon, and Merck; institutional financial interests in the form of consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a DSMB or advisory board from Eli Lilly, MSD, Pfizer (MISP), AstraZeneca, MSD International, BMS, Boehringer Ingelheim Italia, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GSK, and Spectrum pharmaceuticals, Italian Association for Cancer Research, Italian Medicines Agency, Italian Moh, and TRANSCAN; research funding, support for attending meetings, and travel from Merck; and having a leadership or fiduciary role in European Society for Medical Oncology, American Society of Clinical Oncology, and International Association for the Study of Lung Cancer. XH, MK, EO, YL, SL, J-FP, and FS employees and shareholders of Regeneron Pharmaceuticals. GG is a former employee and shareholder of Regeneron Pharmaceuticals. IL and PR are employees of, have a patent pending (PCT/US2018/018747), and are shareholders of Regeneron Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)