Promising outcomes of salvage chemotherapy after nivolumab therapy have been reported; however, little is known about the detailed clinical and immunologic features in lung cancer patients in whom nivolumab is unsuccessful. We report two cases of nivolumab-refractory lung cancer, in which chemotherapy resulted in rapid regression of the lung cancer. Upon initial diagnosis, the biopsy specimens showed PD-ligand 1 (PD-L1)-expressing cancer cells, accompanied by tumor-infiltrating lymphocytes with a favorable CD8/CD4 ratio. Immunosuppressive regulatory T cells and cells positive for TIM-3 were also observed. Physicians should take caution in treating lung cancer patients after progression on nivolumab. Further studies with a large cohort are warranted to identify the patients that may benefit from salvage chemotherapy.