Efficacy of neoadjuvant, adjuvant, and perioperative immunotherapy in non-small cell lung cancer across different PD-L1 expression levels: a systematic review and meta-analysis

Abstract

Background: Immune checkpoint inhibitors, particularly anti-PD-1/PD-L1 monoclonal antibodies, have transformed non-small cell lung cancer (NSCLC) treatment. This meta-analysis evaluates the efficacy of neoadjuvant, adjuvant, and perioperative immunotherapy in resectable NSCLC, stratified by PD-L1 expression levels.

Methods: We conducted a meta-analysis of 10 randomized controlled trials (RCTs) involving 11 articles, focusing on pathological complete response (pCR), major pathological response (MPR), event-free survival (EFS), and overall survival (OS). These outcomes were stratified by PD-L1 expression levels (<1%, ≥1%, 1-49%, ≥50%).

Results: Immunotherapy significantly improved pCR (OR=4.96, 95% CI=2.88-8.57 for PD-L1<1%; OR=9.58, 95% CI=6.32-14.53 for PD-L1≥1%), MPR (OR=2.86, 95% CI=1.97-4.16 for PD-L1<1%; OR=7.39, 95% CI=4.59-11.88 for PD-L1≥1%), and EFS (HR=0.80, 95% CI=0.70-0.92 for PD-L1<1%; HR=0.53, 95% CI=0.45-0.62 for PD-L1≥1%) across all PD-L1 subgroups. Greatest benefits were observed in PD-L1≥50% subgroup, with ORs for pCR and MPR, and HRs for EFS, showing consistent improvements. OS benefits were significant in PD-L1≥1% patients (HR=0.62, 95% CI=0.49-0.79 for PD-L1≥1%) but uncertain in PD-L1<1% cohorts (HR=1.11, 95% CI=0.86-1.44 for PD-L1<1%). Immunotherapy in perioperative setting demonstrated robust efficacy, with significant pathological response and EFS benefits across all PD-L1 subgroups.

Conclusion: This meta-analysis supports immunotherapy within perioperative care for resectable NSCLC, emphasizing PD-L1 expression as a predictive biomarker. Future studies should optimize patient selection and clarify immunotherapy's role in different treatment settings.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42025644497, identifier CRD42025644497.

Keywords: PD-L1 expression; efficacy; immunotherapy; meta-analysis; non-small cell lung cancer.

Figure 1

PRISMA flow diagram for study selection. The flow diagram illustrates the systematic process of identifying, screening, and selecting studies for inclusion in the meta-analysis. A total of 1,598 records were identified through database searching. After removing 492 duplicate records, 1,106 records were screened for eligibility. Of these, 854 reports were sought for retrieval, with 226 basic studies excluded. Following a detailed assessment of 628 reports, 11 papers involving 10 trials were ultimately included in the analysis. The exclusion criteria at each stage are detailed in the flow diagram.

Figure 2

Risk of bias assessment according to the cochrane risk of bias tool (2.0). The risk of bias for each included study is assessed by using the Cochrane Risk of Bias Tool (2.0). The domains assessed include the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Each domain is rated as low risk (+), some concerns ()?, or high risk ()! based on specific criteria.

Figure 3

Forest plots depicting the efficacy of immunotherapy across PD-L1 expression levels of <1% and ≥1%. This figure provides forest plots for the outcomes including (A) pathological complete response (pCR)rate in patients with PD-L1 expression <1%, (B) major pathological response (MPR) rate in patients with PD-L1 expression <1%, (C) event-free survival (EFS) in patients with PD-L1 expression <1%, (D) overall survival (OS) in patients with PD-L1 expression <1%, (E) pCR rate in patients with PD-L1 expression ≥1%, (F) MPR rate in patients with PD-L1 expression ≥1%, (G) EFS in patients with PD-L1 expression ≥1%, and (H) OS in patients with PD-L1 expression ≥1%.

Figure 4

Forest plots depicting the efficacy of immunotherapy across PD-L1 expression levels of 1-49% and ≥50%. This figure provides forest plots for the outcomes including (A) pathological complete response (pCR) rate in patients with PD-L1 expression between 1-49%, (B) major pathological response (MPR) rate in patients with PD-L1 expression between 1-49%, (C) event-free survival (EFS) in patients with PD-L1 expression between 1-49%, (D) overall survival (OS) in patients with PD-L1 expression between 1-49%, (E) pCR rate in patients with PD-L1 expression ≥50%, (F) MPR rate in patients with PD-L1 expression ≥50%, (G) EFS in patients with PD-L1 expression ≥50%, and (H) OS in patients with PD-L1 expression ≥50%.

Figure 5

Cumulative meta-analysis of event-free survival (EFS) across different PD-L1 Expression Levels. This figure illustrates the cumulative meta-analysis results over the years for pooled hazard ratios (HRs) of EFS across various PD-L1 expression levels including (A) PD-L1 expression <1%, (B) PD-L1 expression ≥1%, (C) PD-L1 expression between 1-49%, and (D) PD-L1 expression ≥50%.