Efficacy and safety of perioperative, adjuvant and neoadjuvant chemoimmunotherapy stratified by clinical stage and PD-L1 expression in resectable non-small cell lung cancer: a systematic review and network meta-analysis

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Background: IIIA-IIIB) and programmed cell death ligand 1 (PD-L1) expression. Methods: A systematic literature search was conducted through PubMed, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials up to April 1, 2025. Relevant conference proceedings were also included. Randomized controlled trials (RCTs) comparing two or more treatment options for patients with resectable NSCLC were included. Eligible trials were selected by two researchers independently according to predefined criteria. The Cochrane Collaboration's tool was used to evaluate the risk of bias. Data were extracted following PRISMA guidelines, either a fixed-effect or random-effect model was applied depending on heterogeneity. The primary outcome was event-free survival (EFS). Secondary outcomes included overall survival (OS) and the incidence of grade ≥3 treatment-related adverse events (TRAEs). Subgroup analyses were performed by disease stage, PD-L1 expression and Eastern Cooperative Oncology Group (ECOG) performance status (PS). Results: Twenty-one RCTs involving 12,258 patients with resectable NSCLC were included in this network meta-analysis. The outcomes were evaluated by a Bayesian fixed-effect model. For patients with stage IB-II NSCLC, perioperative chemoimmunotherapy was comparable with adjuvant chemoimmunotherapy [hazard ratio (HR) 1.06, 95% confidence interval (CI): 0.64 to 1.77; P=0.82] and neoadjuvant chemoimmunotherapy (HR 0.78, 95% CI: 0.37 to 1.62; P=0.51) in terms of EFS. In contrast, for patients with stage IIIA-IIIB NSCLC, both perioperative chemoimmunotherapy (HR 0.32, 95% CI: 0.16-0.64; P=0.001) and neoadjuvant chemoimmunotherapy (HR 0.31, 95% CI: 0.14 to 0.69; P=0.004) were associated with significantly improved EFS compared to adjuvant chemoimmunotherapy. All three chemoimmunotherapy strategies showed benefit in PD-L1-positive patients, but only perioperative chemoimmunotherapy significantly improved EFS versus neoadjuvant chemotherapy in PD-L1-negative (tumor proportion score <1%) patients (HR 0.74, 95% CI: 0.60 to 0.91; P=0.005). Additionally, perioperative chemoimmunotherapy was also the only approach that led to significant improvement in EFS for patients with ECOG PS ≥1 (HR 0.55, 95% CI: 0.43 to 0.72; P<0.001). Notably, perioperative chemoimmunotherapy was associated with a higher incidence of grade ≥3 TRAEs compared to neoadjuvant chemoimmunotherapy (OR 1.63, 95% CI: 1.02 to 2.59; P=0.041). Conclusions: Perioperative, adjuvant and neoadjuvant chemoimmunotherapy were all suitable for patients with stage IB-II NSCLC, while perioperative and neoadjuvant chemoimmunotherapy may represent more favorable options for stage III disease. In patients with PD-L1-negative expression or ECOG PS ≥1, only perioperative chemoimmunotherapy was associated with improved EFS versus chemotherapy. Our findings might benefit future individualized immunochemotherapy for resectable NSCLC.

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