International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 224-234 http://medscipublisher.com/index.php/ijmms 2 28 For resectable non-small cell lung cancer, the use of PD-1/PD-L1 inhibitors combined with chemotherapy during neoadjuvant therapy or perioperative period, compared with chemotherapy alone, can increase overall survival rate (HR 0.62-0.66), event-free survival rate and pathological response rate. Subgroup analyses also showed that drugs such as camrelizumab and pembrolizumab might be more effective in specific patient populations (Liu et al., 2025; Fu et al., 2025). 4.3 Evaluation of heterogeneity and publication bias The differences among the included studies are usually evaluated by I² statistics and χ² tests. Although some meta-analyses reported moderate differences (I²to 50%) in overall survival, most analyses showed consistent benefits across trials, and subgroup analyses and sensitivity analyses also demonstrated reliable pooled results. The sources of differences include variations in PD-L1 expression, histological types, and treatment regimens (Li et al., 2020). Researchers used funnel plots and statistical methods to determine whether there was publication bias. The latest meta-analysis found no obvious signs of bias, suggesting that the observed survival advantage was unlikely to be caused by selective reporting or omission of studies (Liu et al., 2025; Fu et al., 2025). The reliability of these results has been further guaranteed through strict quality assessment and comprehensive literature retrieval. 5 Clinical Research and Survival Benefit Results 5.1 Review of key randomized controlled trials (RCTs) A number of large-scale randomized controlled trials have demonstrated that PD-1/PD-L1 inhibitors combined with chemotherapy have a significant effect on the first-line treatment of advanced non-small cell lung cancer (NSCLC). It is worth noting that the network meta-analysis and systematic review integrated the data from major studies such as KEYNOTE-189, KEYNOTE-407 and IMpower130, and the results showed that compared with chemotherapy alone, The addition of PD-1/PD-L1 inhibitors during chemotherapy can significantly improve overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) (Li et al., 2020; Li et al., 2021). For instance, a network meta-analysis involving 9 randomized controlled trials on advanced squamous NSCLC indicated that the OS hazard ratio (HR) of PD-1 inhibitor combined with chemotherapy was 0.70, and the PFS hazard ratio (HR) was 0.50, demonstrating a significant survival advantage (Liu et al., 2025). Among PD-1/PD-L1 inhibitors, the combination of camrelizumab and pembrolizumab with chemotherapy has particularly outstanding effects. In some studies, camrelizumab showed the most significant improvement in OS and PFS (Liu et al., 2025; Fu et al., 2025). These results provide an important basis for the formulation of clinical guidelines and further support the use of chemotherapy combined with immunotherapy as the standard treatment for patients with advanced and partially operable NSCLC. 5.2 Comparison of therapeutic effects among subgroups expressing PD-L1 The survival benefits of PD-1/PD-L1 inhibitors combined with chemotherapy covered all PD-L1 expression subgroups, including patients with low (<1%) or negative expression. Meta-analysis showed that combination therapy could significantly improve OS and PFS in patients with high and low PD-L1 expression. The OS HR (hazard ratio) of the PD-L1-negative population ranged from 0.71 to 0.75 (Figure 2) (Wankhede et al., 2022). This is different from monotherapy. The benefits of monotherapy are mainly reflected only in patients with higher PD-L1 expression (≥50%). Although patients with high PD-L1 expression achieved the greatest absolute benefit, patients with low PD-L1 expression or negative PD-L1 also showed significant improvements in survival rate and response rate after combination therapy (Liu and Zhang, 2025). These results suggest that PD-1/PD-L1 inhibitors combined with chemotherapy can be used regardless of PD-L1 expression, especially in first-line treatment (Wankhede et al., 2022). 5.3 Long-term follow-up and genuine evidence Long-term follow-ups from randomized controlled trials and emerging real-world studies have confirmed that the survival benefits of PD-1/PD-L1 inhibitors combined with chemotherapy are sustained. Extended analysis showed
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