We experienced a patient who had four lung cancers with different pathological features, with the most advanced being diagnosed as pStage IIA. A month after the resection, the original lung cancer had metastasized to the lung and to the liver. Of the original lung cancers that were resected, the biggest adenocarcinoma of S3 showed 50 × 31 × 17 mm (invasion 50 mm) and pT2bN0M0 (pStage IIA) with epidermal growth factor receptor (EGFR) mutation (-) and anaplastic lymphoma kinase (ALK) translocation (-), but expression of programmed death ligand 1 (PD-L1) (+) tumor proportion score (TPS) 80%. The pleomorphic carcinoma showed 23 × 20 × 17 mm (invasion 23 mm) and pT1cN0M0 (pStage Ic) with EGFR (-), ALK (-), PD-L1 (+), TPS 95%. Tumor mutation burden (TMB), microsatellite instability (MSI), and structural chromosome aberration analysis by DNA microarray were performed. One hundred somatic mutations in the adenocarcinoma and 75 somatic mutations in the pleomorphic carcinoma were identified, which showed an extremely high mutation rate, although only 16 somatic mutations were common between the two cancers. Chromosomal structural aberrations differed greatly between the two cancers, but common aberrations were found in chromosomes 8 and 10 and partially common aberration in chromosomes 4, 14, 17, and X. These results indicated that each lung cancer originated from a common ancestor clone and developed on an individual molecular evolution. The patient received a single injection of pembrolizumab and 13 injections of atezolizumab. Immune checkpoint inhibitor treatment made metastatic pulmonary and liver lesions reduce in size and show as Partial response (PR). Multiple lung cancers with high PD-L1 activity tend to be TMB-high, reflecting rapid molecular evolution and relevance to the patient's response to immune checkpoint inhibitors. Genomic examination could help determine what had happened in multiple cancers on progression and provide useful data to patient treatment. Each lung cancer originated from a common ancestor clone and developed on an individual molecular evolution.