Efficacy and safety of PD-1 inhibitors as second-line treatment for advanced squamous esophageal cancer: a systematic review and network meta-analysis with a focus on PD-L1 expression levels.

Background: PD-1 inhibitors have shown promising efficacy in enhancing OS and AEs as second-line therapies for patients with advanced esophageal squamous cell carcinoma (ESCC). However, there remains no clear consensus on which PD-1 inhibitor provides the best balance between efficacy and safety. To address this key issue in the second-line treatment of ESCC, we conducted a network meta-analysis (NMA) with a focus on OS benefits, particularly in patients with different levels of PD-L1 expression. Methods: A systematic search of relevant literature was conducted in Web of Science, Embase, PubMed, and Cochrane Library, covering publications from the inception of these database to June 2024. The evaluated endpoints included OS, progression-free survival (PFS), objective response rate (ORR), AEs, and Grade ≥ 3 adverse events (Grade ≥ 3 AEs). A systematic review and Bayesian network meta-analysis were performed to assess the efficacy and safety of various immunotherapy regimens in patients with advanced ESCC. To ensure transparency, novelty, and reliability, this study was prospectively registered in the systematic review registry (CRD42024540581). Results: Five randomized controlled trials (RCTs), encompassing 2,078 patients and six treatment regimens, were included in this study. Among advanced ESCC patients not selected based on PD-L1 expression, Sintilimab demonstrated the greatest OS benefit (HR = 0.70, 95% CI: 0.50-0.98). Camrelizumab showed the most favorable improvement in PFS compared to chemotherapy (HR = 0.64, 95% CI: 0.47-0.87) and also achieved the best ORR benefit (OR = 3.72, 95% CI: 1.98-6.99). In terms of safety, Nivolumab (OR = 0.10, 95% CI: 0.05-0.19) and Tislelizumab (OR = 0.18, 95% CI: 0.10-0.33) exhibited significant safety advantages over chemotherapy concerning AEs. Moreover, Nivolumab (OR = 0.13, 95% CI: 0.08-0.20) was associated with a markedly lower risk of Grade ≥ 3 AEs compared to chemotherapy. Subgroup analysis based on PD-L1 expression revealed that Tislelizumab (HR = 0.53, 95% CI: 0.37-0.76) offered the greatest OS benefit for patients with PD-L1 ≥ 10%, while Camrelizumab (HR = 0.71, 95% CI: 0.57-0.89) was the most likely regimen to provide an OS advantage for patients with PD-L1 < 10%. Conclusion: Compared to chemotherapy, PD-1 inhibitors may provide improved survival outcomes for patients with advanced ESCC. Among patients not selected based on PD-L1 expression, Sintilimab is most likely to deliver the best survival benefit. For patients with PD-L1 expression ≥ 10%, Tislelizumab is expected to offer the greatest efficacy, while Camrelizumab appears to be the most effective for those with PD-L1 < 10%. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024540581.