[Summary of second-line treatment of stage IV NSCLC without oncogenic addiction]

Stage IV non-small cell lung cancer (NSCLC) without actionable mutations remains a major therapeutic challenge, especially following immunotherapy failure. The introduction of immune checkpoint inhibitors (anti-PD-1/PD-L1) has revolutionized first-line treatment, but second-line options remain largely dependent on older chemotherapies such as docetaxel or pemetrexed. A significant number of patients experience disease progression despite immunotherapy, highlighting tumor resistance mechanisms, whether primary (rapid failure) or acquired (after initial response). Resistance mechanisms include low CD8+ T-cell infiltration, genetic mutations (PTEN, JAK), loss of neoantigens, and tumor-induced immunosuppression. Innovative strategies are under investigation: antibody-drug conjugates (anti-TROP-2, anti-CEACAM-5), cancer vaccines (TEDOPI), external electric fields (TTFields), oncolytic viruses, and PROTACs. While some of these show promise in progression-free survival, global survival benefit remains modest. The identification of robust predictive biomarkers is essential for tailoring future therapies.