Immune checkpoint inhibitors across neoadjuvant, perioperative, and adjuvant settings for resectable non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials

Randomized evidence for immune checkpoint inhibition in resectable non-small-cell lung cancer has progressed from pathological response to mature survival outcomes. We examined exploratory directional alignment across endpoints and quantified clinical yield, treatment burden, and the extent of perioperative therapy delivery. We synthesized 20 peer-reviewed reports from 12 parent randomized trials, including 8,197 unique participants and 13 eligible randomized treatment comparisons. The parent trial was the analysis unit, and the latest compatible report replaced earlier estimates for each time-to-event outcome. Direct randomized comparisons were pooled using restricted maximum-likelihood random-effects models. We reconstructed cumulative event-free survival (EFS) and overall survival (OS) evidence, estimated absolute differences, performed exploratory trial-level cross-endpoint analyses, and pooled the proportion of experimental-arm patients who started postoperative study treatment. Across seven trials, treatment initiated before surgery reduced EFS events by 41% (HR, 0.59; 95% CI: 0.53–0.66; I 2 = 12%). Five trials showed a 32% reduction in death (HR, 0.68; 95% CI: 0.58–0.80; I 2 = 0%). Per 100 randomized patients, preoperative-start therapy produced 31 additional major pathological responses (95% CI: 24–39), 22 additional pathological complete responses (95% CI: 16–27), and 4 additional patients who underwent or attempted curative-intent surgery (95% CI: 1–7). Grade ≥3 treatment-related adverse events increased by approximately 4 per 100 patients (95% CI: 0–8). In exploratory analyses, larger pCR improvements tended to accompany lower EFS HRs (Spearman ρ = −0.67; p = 0.098; k = 7), and EFS and OS estimates were directionally aligned (ρ = 0.95; p = 0.051; k = 4). In six perioperative trials, 69.7% (95% CI: 65.5%–73.7%) of randomized experimental-arm patients started postoperative study treatment. ICI-containing strategies initiated before surgery improve pathological response, EFS, and OS in resectable NSCLC. Approximately 70% of patients assigned to perioperative experimental arms started postoperative study treatment; this descriptive treatment-delivery finding does not establish whether postoperative ICI can be safely omitted. Prospective response- and residual-risk-guided randomized trials are required.