Exploratory Investigation Into Perioperative Treatment Strategies for Potentially Resectable Stage III-N2 Driver Gene-Negative Non-Small Cell Lung Cancer in the Immunotherapy Era.

[BACKGROUND] Comparisons among treatment strategies for potentially resectable Stage III-N2 driver gene-negative non-small cell lung cancer (NSCLC) remain limited. We evaluated three treatment strategies-neoadjuvant chemoimmunotherapy followed by surgery (NCIT+surgery), NCIT followed by chemoradiotherapy (NCIT+CRT), and definitive concurrent chemoradiotherapy followed by immunotherapy (CRT + IT)-to investigate whether CRT could represent a feasible option to surgery.

[METHODS] Patients with Stage III-N2 NSCLC from two institutions (2019-2024) were retrospectively enrolled. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses included metastatic N2 lymph node status, stage, programmed death ligand 1 expression, radiographic response to NCIT, and adjuvant or consolidation immunotherapy after surgery or CRT. Baseline differences were balanced 1:1 by propensity score matching (PSM). Survival was estimated by the Kaplan-Meier method and compared via the log-rank test.

[RESULTS] A total of 363 patients were included: NCIT+Surgery (n = 176), NCIT+CRT (n = 55), and CRT + IT (n = 132). The median follow-up time was 31.5 months. Before and after PSM, PFS, and OS were longer in NCIT+Surgery than in CRT + IT, whereas no significant difference was observed between NCIT+Surgery and NCIT+CRT. Subgroup analysis showed that survival did not differ significantly between NCIT+Surgery and CRT + IT in patients with multistation or bulky N2 metastasis, whereas CRT + IT was associated with inferior PFS and OS in patients without these features.

[CONCLUSIONS] Survival did not differ significantly between CRT and surgery after NCIT, nor between CRT + IT and NCIT + Surgery among patients with multistation or bulky N2 disease. Whether CRT can serve as an alternative to surgery in this population requires validation in large-scale prospective studies.