A Quarter Century of Transformation: Integrating Molecular Stratification and Immune Modulation Across the Continuum of Non–Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) has seen a paradigm shift over the past quarter century driven by systematic molecular characterization, the advent of targeted therapies, the implementation of low-dose CT screening, and the integration of immunotherapy across the disease continuum. Genomic profiling has defined oncogene-addicted subsets for which targeted agents now improve survival in both metastatic and resectable disease, while immune checkpoint inhibitors have displaced chemotherapy as first-line treatment for many patients without actionable drivers and have been incorporated into perioperative and consolidation strategies. Concurrently, adjuvant and consolidation tyrosine kinase inhibition has extended precision oncology into early-stage EGFR- and ALK-driven NSCLC. Here, we review pivotal therapeutic advances across metastatic, locally advanced, and early-stage disease; identify the need for more discriminating markers to refine treatment intensity and sequencing; and outline emerging approaches, including rational upfront combinations and the use of circulating tumor DNA to enable real-time, adaptive modulation of therapy in NSCLC.