Real-world insights into multidisciplinary management and outcomes of stage III (N2–3) non-small cell lung cancer

Background: Stage III (N2-3) non-small cell lung cancer (NSCLC) represents a highly heterogeneous group, with limited evidence to guide multidisciplinary management in real-world settings. This study aimed to evaluate treatment patterns and associated pathological and survival outcomes in this population. Methods: This study analyzed patients with stage III (N2-3) NSCLC treated at our center between 2009 and 2024. All patients had pathologically confirmed mediastinal lymph node involvement and received neoadjuvant therapy. Treatment patterns, pathological responses, and survival outcomes were systematically assessed. Survival was estimated using the Kaplan-Meier method, and prognostic factors were identified with Cox regression analyses. Results: A total of 243 eligible patients were included. Treatment allocation was stratified by oncogenic driver status, with 75 receiving neoadjuvant immunotherapy-chemotherapy (IO-chemo), 46 targeted therapy, and 122 chemotherapy. Following neoadjuvant treatments, 175 patients (72.0%) underwent surgical resection, 46 (18.9%) received radiotherapy, and 22 (9.1%) continued systemic therapy. The IO-chemo group had the most surgical patients (77.3%) and demonstrated superior pathological responses among resected cases, with pathological complete response (pCR) and major pathological response (MPR) rates of 34.5% and 48.3%, respectively. Median event-free survival (EFS) and overall survival (OS) for the entire cohort were 28.7 months and 67.2 months. Patients treated with chemotherapy had worse survival compared with those treated with IO-chemo and targeted therapy, while survival outcomes were similar between the latter two groups. Multivariate analysis identified neoadjuvant IO-chemo as an independent favorable factor for both EFS and OS. At last, maintenance therapy following surgery or radiotherapy was associated with improved survival. Conclusions: In this real-world cohort of stage III (N2-3) NSCLC, novel neoadjuvant therapies, including IO-chemo and targeted therapy, achieved superior pathological responses and improved survival compared with chemotherapy. Importantly, even patients with N3 disease derived meaningful benefit from surgery when combined with effective neoadjuvant treatment.