Background: It has been noted that positive results from ramucirumab (RAM) plus docetaxel (DOC) combination therapy for advanced non-small-cell lung cancer (NSCLC) are linked to a history of immune checkpoint inhibitor pre-administration. Nevertheless, nothing is now known about the therapeutic importance of RAM and DOC after combined chemoimmunotherapy. Thus, following combination chemoimmunotherapy, we assessed the safety and effectiveness of RAM + DOC therapy and tried to determine the factors that might influence its results. Patients and Methods: Following combination chemotherapy and immunotherapy, this multi-center prospective trial examined the safety and effectiveness of RAM plus DOC. PFS, or progression-free survival, was the main outcome. The objective response rate (ORR), disease control rate (DCR), overall survival (OS), and adverse event incidence were secondary objectives. Serum cytokine levels were assessed at the beginning of treatment in an exploratory investigation. Results: Between April 2020 and June 2022, a total of 44 patients from 10 Japanese institutions were enrolled. The median OS was 22.6 months, whereas the median PFS was 6.3 months. Additionally, the DCR was 72.7% and the ORR was 36.4%. The PFS and OS were noticeably worse in the group with elevated vascular endothelial growth factor D (VEGF-D). A prolonged PFS was linked to both low and high levels of VEGF-D and VEGF-A. Conclusion: our findings suggested that RAM with DOC following combination chemoimmunotherapy could be a practical and successful second-line treatment for patients with advanced non-small cell lung cancer in the real world.