Efficacy and safety of perioperative, neoadjuvant, or adjuvant immunotherapy alone or in combination with chemotherapy in early-stage non-small cell lung cancer: a systematic review and meta-analysis of randomized clinical trials

Background: Neoadjuvant (NE), adjuvant (AD), and perioperative (PE) immunotherapies have gained validation in early-stage non-small cell lung cancer (NSCLC) trials. However, a comprehensive assessment of their comparative efficacy and safety is lacking. Objectives: To compare the efficacy and safety of NE, AD, and PE immunotherapies in early-stage NSCLC. Design: A systematic review and network meta-analysis using a Bayesian framework. Data sources and methods: We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) of immune checkpoint inhibitors plus chemotherapy (CT) for early-stage NSCLC. Hazard ratios (HRs) and odds ratios (ORs) for binary endpoints with 95% confidence intervals (CIs) were calculated. Results: We included 10 RCTs involving 5569 NSCLC patients, categorized as NE, PE, or AD immunotherapy. Indirect comparisons highlighted differences in efficacy between PE and AD immunotherapy, specifically in event-free survival (EFS)/disease-free survival (DFS) (HR = 0.72, 95% CI: 0.53-0.96). NE/PE immunotherapies improved pathologic complete response (pCR) (OR = 7.56, 95% CI: 5.24-10.92), major pathologic response (MPR) (OR = 5.46, 95% CI: 3.97-7.51), and EFS (HR = 0.58, 95% CI: 0.52-0.65), while AD immunotherapy enhanced DFS (HR = 0.78, 95% CI: 0.69-0.90). Overall survival (OS) benefits were seen only with PE immunotherapy (HR = 0.66, 95% CI: 0.55-0.81). PE treatment improved EFS across various subgroups (PD-L1 < 1%, IIIB, squamous, female, without MPR/pCR, epidermal growth factor receptor (EGFR) mutant-negative), except EGFR mutant-positive NSCLC (HR = 0.54, 95% CI: 0.21-1.43). AD (OR = 1.81, 95% CI: 1.20-2.73) and PE (OR = 1.28, 95% CI: 1.10-1.50) immunotherapies were associated with higher grade ⩾3 adverse events. Conclusion: In the three treatment modalities, PE immunotherapy appears to be more effective than AD immunotherapy, with PE showing significant advantages in certain subgroups that NE does not. NE and PE immunotherapy significantly improved pCR, MPR, and EFS, while AD immunotherapy significantly improved DFS in NSCLC patients compared to the control group. However, only PE immunotherapy significantly improved OS. Differences in efficacy between NE and PE across the entire population of resectable NSCLC remain to be explored in additional studies.