Risk-adaptive management of stage III NSCLC in the perioperative immunotherapy era: a critical synthesis and clinical framework

Abstract

Stage III non-small cell lung cancer (NSCLC) is a highly heterogeneous disease, and recent phase III trials have demonstrated the efficacy of neoadjuvant and perioperative chemoimmunotherapy in selected patients. However, translating these data into consistent real-world multidisciplinary decision-making remains challenging because anatomical resectability, nodal burden, tumor biology, and treatment response vary substantially. Neoadjuvant nivolumab plus chemotherapy significantly improved pathological complete response and event-free survival (EFS), with a modest but clinically meaningful overall survival (OS) benefit at five years. Perioperative strategies appear to extend these benefits: KEYNOTE-671 demonstrated a significant OS advantage, while AEGEAN and CheckMate 77T showed consistent EFS improvements, with OS data still maturing. However, cross-trial comparisons are inherently limited, and the incremental contribution of the adjuvant immunotherapy phase remains unclear. Exploratory subgroup analyses suggest potentially greater benefit in N2 disease, although prospective validation is required. For tumors harboring actionable oncogenic alterations, upfront resection followed by adjuvant targeted therapy remains the preferred strategy, whereas definitive chemoradiotherapy followed by consolidation durvalumab remains standard of care for unresectable stage III disease. Management of stage III NSCLC should be individualized through multidisciplinary assessment. Major uncertainties persist regarding the comparative efficacy of perioperative versus neoadjuvant-only strategies, the contribution of adjuvant immunotherapy, and the role of biomarker-guided treatment adaptation. This clinical framework provides structured guidance to support treatment selection across the heterogeneous spectrum of stage III disease, while recognizing that prospective validation of risk-adapted strategies remains essential.