Equivalence of neoadjuvant and perioperative therapies in patients with stage III non-small cell lung cancer: a systematic review and meta-analysis.

Both neoadjuvant and perioperative immunotherapies have emerged as standard-of-care treatments for patients with resectable non-small cell lung cancer (NSCLC). However, the optimal treatment strategy regarding the necessity of the adjuvant phase remains undefined due to a lack of direct head-to-head comparisons. This study thus aimed to quantitatively evaluate whether extending immunotherapy into the adjuvant phase confers a survival benefit over neoadjuvant therapy alone in patients with stage III NSCLC. A systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted for randomized controlled trials (RCTs) published as of June 21, 2025. Individual patient data (IPD) were reconstructed from Kaplan-Meier (KM) curves of the eligible studies. The primary end points were event-free survival (EFS) and overall survival (OS). Statistical analyses included stratified log-rank tests, Cox proportional hazards regression, and restricted mean survival time (RMST) analysis. Seven studies (six RCTs and one single-arm phase II trial) involving 1,436 patients with stage III NSCLC were included in the analysis. In the overall population, neoadjuvant and perioperative immunotherapies demonstrated comparable efficacy, with no significant difference in EFS [hazard ratio (HR) =0.99; 95% confidence interval (CI): 0.72-1.36; P=0.94]. Subgroup analysis indicated stage-dependent outcomes: EFS was similar in the stage IIIA cohort (HR =1.04; P=0.87), whereas a nonsignificant advantage for neoadjuvant therapy was observed in the mixed-stage IIIA-IIIB cohort (HR =0.52; 95% CI: 0.27-1.03; P=0.05). In the analysis of OS, which was restricted to the stage IIIA population due to data maturity, no significant difference was found between the two strategies (HR =0.97; 95% CI: 0.58-1.64; P=0.92). The 5-year RMST of OS was 48.51 months for the neoadjuvant group and 47.56 months for the perioperative group (difference =0.95 months; P=0.69). The findings from this IPD-based quantitative analysis suggest that neoadjuvant immunotherapy may yield EFS and OS outcomes comparable to those of perioperative immunotherapy in patients with resectable stage III NSCLC. However, given the indirect nature of the comparison, these results should be considered hypothesis-generating; they provide a rationale for investigating a neoadjuvant-only strategy as a potential de-escalation approach. Future head-to-head trials are warranted to validate these findings, particularly among patients with stage IIIB disease.