Herein, we report a case of unresectable lung cancer in which S-1 monotherapy contributed to an improvement in the patient's quality of life and to prolonged survival. A 44-year-old man with primary pulmonary adenocarcinoma(negative driver mutation and a PD-L1 tumor proportion score of 1-24%)of clinical stage ⅢA(cT4N0M0)underwent multidisciplinary treatment as follows: 1 ) weekly carboplatin and paclitaxel plus radiotherapy as induction chemoradiotherapy, 2 ) surgery that revealed that the lesion was unresectable, 3 ) cisplatin plus pemetrexed as second-line treatment, and 4 ) pembrolizumab as third-line treatment. However, the disease progressed after 19 courses of pembrolizumab, and the patient developed cachexia due to esophageal stenosis caused by tumor enlargement. He underwent percutaneous gastrostomy and was fed via a gastrostomy tube. S-1 monotherapy(2-week administration every 3 weeks)was introduced as fourth-line treatment. After 3 courses of S-1 monotherapy, the patient complained of regurgitation of stomach fluid. Computed tomography( CT)revealed that the primary tumor had decreased in size, and he developed the ability to drink water. After 6 courses of S-1, CT revealed progressive disease, so atezolizumab was administered as fifth-line treatment. However, after 2 courses, mediastinitis due to esophageal penetration into the mediastinum occurred. The patient died 28 months after the initial treatment.