A systematic review and network meta-analysis of immune checkpoint inhibitors in operable NSCLC: neoadjuvant, adjuvant, or perioperative?

BACKGROUND

The optimal timing for immune checkpoint inhibitor (ICI) therapy in patients with operable non-small cell lung cancer (NSCLC) remains a subject of clinical uncertainty. This Bayesian network meta-analysis (NMA) aimed to compare the efficacy of ICIs administered in neoadjuvant, adjuvant, and perioperative settings.

METHODS

A systematic review of randomized controlled trials (RCTs) published up to September 1, 2024, identified eight eligible studies comprising a total of 3,659 patients. Primary outcomes included disease-free survival (DFS) and event-free survival (EFS). A Bayesian framework was used to estimate hazard ratios (HRs) and 95% credible intervals (CrIs), with treatment efficacy ranked using the surface under the cumulative ranking curve (SUCRA). Risk of bias was assessed using the Cochrane Risk of Bias tool, and sensitivity analyses confirmed the robustness of the findings after exclusion of studies at higher risk.

RESULTS

Perioperative ICIs demonstrated superior efficacy compared with neoadjuvant or adjuvant strategies. Specifically, perioperative toripalimab plus chemotherapy ranked first (SUCRA =0.99; rank 1 probability =87%), followed by perioperative nivolumab (SUCRA =0.94). Both regimens significantly reduced the risk of disease recurrence or progression compared to surgery alone or standard chemotherapy. While neoadjuvant and adjuvant ICIs provided moderate benefit, they ranked lower in overall efficacy. Sensitivity analyses excluding higher-risk studies did not substantially alter the results, confirming their robustness. No direct comparisons were available between all strategies, and heterogeneity in control arms, ICI agents, programmed death ligand-1 (PD-L1) inclusion thresholds, and follow-up duration limit cross-trial comparability. Additionally, long-term overall survival data were largely immature across studies.

CONCLUSIONS

These findings suggest that perioperative administration of ICIs, particularly toripalimab and nivolumab in combination with chemotherapy, may offer the most effective approach to improving DFS/EFS in resectable NSCLC. However, further head-to-head trials, longer follow-up, and biomarker-stratified analyses are needed to confirm these results and guide personalized treatment decisions.