Globally, lung cancer presents a notable incidence and mortality, with approximately 2.2 million new cases and 1.8 million deaths reported annually, which raises significant public health concerns (1, 2). Non-small cell lung cancer (NSCLC), the most prevalent subtype, accounts for 80%-85% of all lung cancer cases (2).The diagnosis of a majority of NSCLC cases occurs at an advanced stage, leading to a dismal prognosis, characterized by a less than 5% five-year survival rate (3). Some patients suffer from locally advanced or metastatic NSCLC, making surgical resection impractical. Standard treatments for such cases often involve platinum-based paclitaxel chemotherapy and/or radiation therapy (4). However, despite the implementation of these therapeutic strategies, a significant proportion of patients fail to achieve favorable outcomes (5).

In the recent past, the advent of immune checkpoint inhibitors (ICIs) has extended the survival period of NSCLC patients with manageable adverse effects (6, 7). ICIs encompass inhibitors targeting programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (8). Compared to ICIs, chemotherapy may more readily induce drug resistance in patients, potentially contributing to the superior efficacy observed with ICIs (9). This disparity in efficacy might be partly attributed to the differing mechanisms of action between the two treatment modalities. ICIs modulate the immune system by blocking the PD-1/PD-L1 pathway, thereby enhancing immune response (10). This immunomodulation may lead to a more sustained anti-cancer response, reducing adaptive resistance of tumor cells to the treatment (10). In contrast, chemotherapy primarily achieves therapeutic effects by directly destroying cancer cells, but its nonspecific nature might make patients more prone to developing drug resistance (8, 11). NSCLC can be pathologically categorized into squamous non-small cell lung cancer (Sq-NSCLC) and non-squamous cell lung cancer (NS-NSCLC). Patients with these subtypes demonstrate disparities in smoking history, tumor location, and clinical outcomes (12). Therefore, personalized treatment based on the distinct characteristics of each cancer subtype is imperative. In contrast to NS-NSCLC, Sq-NSCLC poses greater therapeutic challenges. Diagnosis often coincides with the presence of comorbidities such as chronic obstructive pulmonary disease and cardiovascular conditions, intensifying the complexity of treatment (13–15). PD-L1 has emerged as a potential prognostic factor and biomarker for predicting which patients are more likely to respond to immunotherapy in NSCLC, thereby refining the target population for potential benefits (16–18). Approximately 30% of advanced NSCLC patients exhibit positive PD-L1 expression (PD-L1 expression ≥50%) as detected by immunohistochemistry (IHC) testing (19).

Presently, for stage IV NSCLC without driver gene mutations and with PD-L1 expression ≥50%, pembrolizumab stands as the preferred first-line treatment option (20). Additionally, due to the lack of randomized controlled trials (RCTs) directly comparing various immune checkpoint inhibitors, selecting the optimal immunotherapeutic approach remains challenging. Nevertheless, ambiguity remains regarding the optimal initial treatment for squamous NSCLC exhibiting PD-L1 expression ≥50%. To address this uncertainty, our study employs network meta-analysis (NMA) to compare the efficacy of various first-line immunotherapy approaches, aiming to identify the most effective treatment regimen. This research endeavors to furnish evidence-based guidance for clinical drug selection and offer improved treatment options for patients with squamous NSCLC.

The NMA adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement (21). Utilizing Bayesian methods, we conducted indirect comparisons of treatment modalities that lacked direct comparisons in clinical trials (22). This approach facilitated the generation of probabilistic predictions for treatment outcomes. For the sake of transparency, reliability, and originality, the study protocol has been prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the reference number CRD42022349712.

Following searches in the PubMed, Web of Science, Embase, and Cochrane Library databases, a total of 4198 articles were identified. Post removal of duplicates, 1982 articles were excluded from the analysis. The final selection process is depicted in Figure 1 , with 9 RCTs being chosen for NMA. This study encompasses 9 RCTs, involving 2170 patients, and assesses 10 treatment regimens for Sq-NSCLC: pembrolizumab (pem), chemotherapy (chemo), pembrolizumab plus chemotherapy (pem-chemo), nivolumab plus ipilimumab (nivo-ipi), atezolizumab plus chemotherapy (atezo-chemo), cemiplimab (cemi), pembrolizumab plus ipilimumab (pem-ipi), camrelizumab plus chemotherapy (camre-chemo), tislelizumab plus chemotherapy (tisle-chemo), and sintilimab plus chemotherapy (sinti-chemo). Detailed results are outlined in Table 1 .

This study conducts an extensive NMA to investigate first-line immunotherapy in advanced Sq-NSCLC patients with PD-L1 expression ≥50%. Sq-NSCLC, being more complex compared to NS-NSCLC, is influenced by various factors, including smoking, leading to a higher mutation rate (37). This serves as the justification for concentrating on this specific patient population.

Recognized as a robust predictive biomarker, PD-L1 expression has proven influential, with NSCLC patients showcasing high PD-L1 expression frequently demonstrating a more favorable response to immune checkpoint inhibitors. Therefore, this study explicitly focuses on patients with PD-L1 expression of 50% or higher (38). The goal of this research is to establish a more efficient and personalized first-line immunotherapy strategy for patients with squamous Sq-NSCLC featuring PD-L1 expression of 50% or higher. In the absence of direct head-to-head clinical trials comparing various ICIs, NMA serves as a complementary extension to traditional meta-analysis. NMA utilizes indirect comparisons of interventions from RCTs to rank the efficacy of different ICIs (39).

This study demonstrates that, as a first-line immunotherapy regimen, the combination of camrelizumab and chemotherapy attains optimal values for OS and PFS in patients with advanced Sq-NSCLC exhibiting programmed death-ligand 1 expression of 50% or higher. This is consistent with findings from other NMA that suggest the combination of ICIs and chemotherapy provides the most effective outcomes in the first-line treatment of advanced NSCLC patients with positive PD-L1 expression (40). Pharmacologically, chemotherapy works by directly eliminating cancer cells and inhibiting their proliferation and division, while ICIs block the interaction between PD-1 and PD-L1/PD-L2, thereby inhibiting immune escape (41). These distinct mechanisms, acting synergistically through multiple pathways, enhance treatment effectiveness (41). In a comprehensive NMA study, pembrolizumab emerged as the preferred first-line immunotherapy for advanced NSCLC patients with positive PD-L1 expression, a result that contrasts with the outcomes observed in this study (42). After careful review, it is noted that the published NMA referenced above is from 2021, while the CameL-Sq randomized controlled trial featuring camrelizumab plus chemotherapy was published in 2022. Consequently, the camrelizumab plus Chemotherapy treatment modality was not included in this NMA. It is important to highlight that this NMA primarily focuses on NSCLC patients with PD-L1 expression ≥50%, whereas our study specifically centers on patients with Sq-NSCLC who also exhibit PD-L1 expression ≥50%. In a network meta-analysis, researchers posit that among first-line immunotherapy treatments for NSCLC patients with high PD-L1 expression (≥50%), the use of atezolizumab holds the highest probability of achieving the longest overall survival (OS) (43). Notably, this analysis, published in 2021, does not incorporate the CameL-Sq randomized controlled trial. This underscores the significance of our study, not only contributing to the advancement of personalized treatment approaches but also enhancing the reliability of conclusions by incorporating additional RCTs. Furthermore, this study notes that pembrolizumab, when employed as a first-line treatment for advanced Sq-NSCLC patients with positive PD-L1 expression, exhibits favorable PFS values (HR, 0.35; 95% CI, 0.17–0.72). This study demonstrates that atezolizumab with chemotherapy, when utilized as a first-line treatment for advanced Sq-NSCLC patients with PD-L1-positive expression, exhibits favorable overall survival outcomes (HR, 0.48; 95% CI, 0.28–0.80). In a network meta-analysis evaluating PD-(L)1 inhibitors as monotherapy for first-line treatment in NSCLC patients with high PD-L1 expression, researchers identified cemiplimab as the top-ranking agent for OS, followed by atezolizumab and pembrolizumab (42). In another network meta-analysis assessing immune monotherapy as a first-line treatment for advanced NSCLC patients with PD-L1 expression ≥50%, researchers found that cemiplimab and pembrolizumab exhibited favorable performance in terms of progression-free survival, overall survival, and overall response rate (ORR) (44). In our current study, cemiplimab also demonstrated favorable performance in OS (HR, 0.48; 95% CI, 0.30–0.77). These findings underscore the efficacy of cemiplimab as a monotherapy for the treatment of Sq-NSCLC patients with high PD-L1 expression.

The head-to-head meta-analysis conducted in this study reveals that, for squamous advanced NSCLC patients with PD-L1 expression ≥50%, first-line treatment with ICIs leads to better OS and PFS values compared to chemotherapy, consistent with previous meta-analysis findings (45). This further supports the notion that NSCLC patients with positive PD-L1 expression may experience certain advantages with ICIs over chemotherapy (46).This consistent trend across studies supports the growing understanding of the potential benefits associated with ICIs in this particular patient population, emphasizing the relevance of immunotherapy in the management of advanced NSCLC with elevated PD-L1 expression.

While this study provides valuable insights into personalized treatment strategies for first-line immunotherapy in NSCLC, it is imperative to recognize certain limitations. Firstly, all the RCTs included in this study reported PFS values, but only five reported OS values. This limited availability of OS data may restrict our ability to indirectly compare some treatment regimens based on OS, introducing a potential constraint to our conclusions. Secondly, diverse RCTs in this study utilized different approaches to detect PD-L1 expression in patients. Moreover, in certain trials, researchers did not explicitly specify the method employed to assess PD-L1 expression. The diverse methods for examining PD-L1 expression may lead to misclassification errors. As an example, the utilization of the SP142 assay to detect PD-L1 expression in tumor cells has demonstrated restricted sensitivity, which could potentially affect the precision of the study (47). Thirdly, safety data pertaining to PD-L1 expression of 50% or higher in advanced Sq-NSCLC, which were not documented in the incorporated RCTs, were not subject to assessment in this study. Fourthly, this study utilized OS and PFS values as outcome measures, but it is noteworthy that these may not fully encompass all treatment benefits for patients. When assessing the efficacy of immunotherapy, consideration of other crucial indicators such as quality of life and mental health is warranted. Unfortunately, these aspects are often overlooked by researchers due to the lack of standardized measurement criteria. Finally, due to the limited number of RCTs reporting the efficacy of ICIs in PD-L1 expression ≥50% squamous NSCLC in this study, caution is advised in interpreting the conclusions. This study provides substantial support for advancing personalized treatment strategies, furnishing a wealth of evidence-based guidance for making informed decisions regarding first-line immunotherapy in clinical practice for patients with squamous non-small cell lung cancer. The future direction of development not only includes PD-L1 expression, but also involves identifying predictive biomarkers for treatment response through tumor molecular analysis, such as EGFR mutations in NSCLC (48).

In future research, it is crucial to expand the sample size of RCTs, emphasize standardized PD-L1 expression detection methods, and comprehensively consider a broader array of clinical indicators. Additionally, a comprehensive consideration of a broader array of clinical indicators beyond traditional survival measures is warranted. This inclusive approach will enable a thorough and nuanced evaluation of the application of immunotherapy in patients with squamous NSCLC, shedding light on potential benefits beyond conventional endpoints and fostering a more comprehensive understanding of treatment outcomes.

This study suggests that in patients with Sq-NSCLC expressing PD-L1 at a level of 50% or higher, the initial immunotherapy selection of camrelizumab in combination with chemotherapy produces superior OS and PFS values. Additionally, for this patient subset, the use of ICIs demonstrates superior efficacy compared to chemotherapy.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

WC: Conceptualization, Data curation, Software, Writing – original draft, Writing – review & editing. HL: Conceptualization, Data curation, Supervision, Writing – original draft, Writing – review & editing. YWL: Methodology, Validation, Writing – review & editing. WX: Data curation, Software, Writing – review & editing. SF: Validation, Writing – review & editing. JS: Formal Analysis, Validation, Writing – review & editing. SL: Data curation, Supervision, Writing – review & editing. YL: Visualization, Writing – review & editing. LZ: Supervision, Writing – review & editing.