Comparative safety profiles of first-line immunotherapy regimens in advanced esophageal squamous cell carcinoma: a network meta-analysis focusing on toxicity stratification.

Background: The combination of immune checkpoint blockade and chemotherapy significantly improves survival when used as first-line treatment for advanced esophageal squamous cell carcinoma. Nonetheless, the safety profiles of various immune checkpoint inhibitor (ICI)-based combination therapies remain inadequately characterized, particularly regarding the incidence of severe adverse events (AEs) and immune-related adverse events (irAEs). The research employed a network meta-analysis to systematically evaluate and contrast the toxicity profiles across various initial ICI-driven treatments for advanced Esophageal squamous cell carcinoma (ESCC). Methods: An extensive literature review was conducted across PubMed, EMBASE, the Cochrane Library, and Web of Science to identify RCTs evaluating first-line immunotherapy in advanced ESCC. The search included all records from each database's inception to July 1, 2025. Primary endpoints included grade ≥3 treatment-related adverse events(grade ≥3 trAEs), any-grade irAEs, and grade ≥3 irAEs. Secondary analyses focused on organ-specific irAEs, including immune-mediated rash, hypothyroidism, hyperthyroidism, and pneumonitis. We conducted a Bayesian network meta-analysis to assess relative risks (RRs) and establish a treatment ranking based on Surface Under the Cumulative Ranking Curve (SUCRA) metrics, evaluating the comparative effectiveness of different therapeutic options. The study protocol was prospectively registered with PROSPERO (CRD420251113069). Results: Seven randomized controlled trials involving 4,479 patients with advanced ESCC were included. In pairwise meta-analyses, ICI plus chemotherapy, compared with chemotherapy alone, increased the risk of grade ≥3 treatment-related adverse events (RR 1.08, 95% CI 1.00-1.17), any-grade irAEs (RR 2.04, 95% CI 1.71-2.44), and grade ≥3 irAEs (RR 2.75, 95% CI 1.98-3.82). Immune-chemotherapy also significantly elevated the risks of immune-mediated rash, hypothyroidism, and hyperthyroidism, whereas the increase in immune-mediated pneumonitis did not reach statistical significance. In Bayesian network meta-analyses, camrelizumab plus chemotherapy had the highest probability of being the regimen with the lowest risk of grade ≥3 trAEs(SCURA = 87.8%) and grade ≥3 irAEs(SCURA = 71.6%), while toripalimab plus chemotherapy ranked safest for any-grade irAEs(SCURA = 83.8%). Conclusions: First-line ICI-based regimens for advanced ESCC are associated with an increased risk of severe treatment-related and immune-related toxicities compared with chemotherapy alone, and their safety profiles differ substantially across regimens. Our SUCRA-based rankings provide a comparative overview of regimen-level toxicity that may assist clinicians in understanding relative safety trade-offs when selecting first-line therapy. These findings should be integrated with regimen-specific efficacy data, regulatory indications, PD-L1 status, comorbidities, and patient preferences, and are best interpreted as complementary safety evidence rather than stand-alone treatment recommendations. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD420251113069.