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¹Department of Radiation Oncology, University of Health Sciences, Dr. Suat Seren Chest Diseases and Surgery Research and Training Hospital, İzmir-Türkiye DOI : 10.5505/tjo.2025.2 The rapid integration of new molecularly targeted therapies and immune checkpoint inhibitors has fundamentally transformed the management of non?small cell lung cancer (NSCLC) across all stages. In earlystage disease, biomarker-driven strategies now enable adjuvant osimertinib for EGFR-mutated tumors and adjuvant alectinib for ALK-rearranged tumors, while neoadjuvant and perioperative chemo-immunotherapy have improved pathologic response and survival outcomes in driver-negative disease. In unresectable stage III NSCLC, concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab remains the standard for driver-negative patients. By contrast, in EGFR-mutated tumors, consolidation osimertinib after chemoradiotherapy (CRT)?supported by the LAURA trial?has produced a marked improvement in progression-free survival, redefining care for this molecular subset. For ALK-rearranged unresectable tumors, the role of targeted consolidation is under active investigation, with retrospective series favoring ALK tyrosine kinase inhibitor strategies over immunotherapy consolidation. In oligoprogression?particularly on TKIs?stereotactic body radiotherapy (SBRT) can eradicate resistant clones, prolong systemic benefit, and allow continuation of the same systemic agent. In patients with brain metastases harboring targetable alterations, the high intracranial activity of contemporary EGFR and ALK TKIs supports deferred radiotherapy in carefully selected patients. Despite these advances, critical questions persist regarding optimal sequencing, timing, treatment duration (including the appropriate length of adjuvant targeted therapy), and the safest, most effective integration of RT with novel agents. This review synthesizes current evidence and evolving strategies for combining new systemic agents and RT in NSCLC, offering a pragmatic, stage- and biology-specific framework to guide multidisciplinary decision-making. Keywords : Immune checkpoint inhibitors; lung cancer; radiotherapy; targeted therapies