Advanced non-small cell lung cancer (NSCLC) remains a high unmet medical need. The first line standard-of-care therapy comprises concurrent chemotherapy-immunotherapy with pembrolizumab. Concurrent irradiation with pembrolizumab has been shown to significantly improve survival benefit compared with immunotherapy alone in a pooled analysis of 2 randomized phase 2 trials. We present the rationale and study design of the "PD-1 iNhibitor and chemotherapy with concurrent IRradiation at VAried tumor sites in advanced Non-small cell lung cAncer" (NIRVANA-Lung) trial (ClinicalTrials.gov identifier, NCT03774732). This study is a national multicenter 1:1 randomized phase III trial testing in 460 patients, the addition of multisite radiotherapy in advanced NSCLC treated with standard immune checkpoint inhibitors (pembrolizumab)-chemotherapy in first line. The primary objective of the trial is to compare the overall survival between the 2 arms at year 1 of the study. The secondary objective is to compare the progression-free survival and cancer-specific survival at year 1 and 2, as well as to determine quality of life, local and distant control in irradiated and nonirradiated sites at 6 months and year 1.