Background: Advances in the treatment of non-small cell lung cancer in the last 5 years (new techniques in radiotherapy, including stereotactic ablative radiotherapy, new targeted therapies and advances in immunotherapy) have increased the survival rates of patients diagnosed with this disease. Methods: Our study refers to a patient diagnosed in July 2017 with stage IV A lung cancer, cT3 N3 M1b (poorly differentiated adenocarcinoma, EGFR, ALK and PDL 1 negative), who underwent five lines of treatment and who has, at the time of writing this article (March 2025), a very good performance status, currently undergoing maintenance chemotherapy. Results: The results obtained confirm the revolutionary role of immunotherapy, but also the importance of chemotherapy and external radiotherapy, suggesting the synergistic effect between these three therapies. We also performed a literature review, highlighting the resistance to immunotherapy, rechallenge with immunotherapy, progression of metastatic NSCLC after first-line chemo-immunotherapy and the role of chemotherapy in line II and III after progression of NSCLC to immunotherapy. Conclusions: Results of studies evaluating new agents and their combinations, along with analysis of the mechanisms of evolution of primary and acquired resistance to immunotherapy are awaited, with the aim of selective and personalized treatment options to improve the survival and the quality of life for this category of patients.