Evaluating the Efficacy and Safety of Immune Checkpoint Inhibitors in First and Second-Line Treatments for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma: A Systematic Review and Network Meta-Analysis of RCTs with a Focus on PD-L1 Expression

Wei Chen ¹ Qiance Wei ^2* Tong Xiao ^3* Jinghan Lai ^4* Mengmeng Huang ^1* Yueran Ma ^5* Lili Zhang ^1* Wenxin Xue ^1* Shui Liu ¹ Lichaoyue Sun ⁶ Wenshu Li ⁷ Zhijun Bu ⁸ Junge Lou ⁹ Zhaolan Liu ^8*

• ¹ Department of Pharmacy, Emergency General Hospital, Beijing, China
• ² Beijing Anzhen Hospital, Capital Medical University, Chaoyang District, Beijing, China
• ³ School of Basic Medical Sciences, Capital Medical University, Beijing, Beijing Municipality, China
• ⁴ Beijing Luhe Hospital, Capital Medical University, Beijing, Beijing Municipality, China
• ⁵ Fuxing Hospital, Capital Medical University, Beijing, China
• ⁶ Pharmacy Department, Aerospace Center Hospital,, beijing, China
• ⁷ Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
• ⁸ Centre for Evidence-Based Chinese Medicine, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
• ⁹ Department of ultrasound Medicine, Zhengzhou Central Hospital affiliated to Zhengzhou University, Zhengzhou, Henan Province, China

Introduction: This study systematically reviewed and conductedperformed a network meta-analysis to assess the efficacy and safety of first-line and second-line immunotherapy treatments for recurrent and metastatic hHead and nNeck sSquamous cCell cCarcinoma (R/M HNSCC). The findings aim to provide robust evidence to guide clinical decision-making.The findings provide robust evidence to support clinical decision-making.Methods: We conducted an comprehensiveextensive literature search in PubMed, Embase, Cochrane Library, and Web of Science. The outcome measures included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 or higher adverse events (AEs ≥3). To compare the efficacy and safety of various first-line and second-line immunotherapy regimens for R/M HNSCC with different PD-L1 expression levels, we conductedperformed a Bayesian network metaanalysis. This study is registered in the Prospective Register of Systematic Reviews (CRD42024551711).Results: This analysis includedThis study encompassed 9 randomized controlled trials (RCTs) involving 5,946 patients and seven immunotherapy regimens. Among patients with R/M HNSCC who were not selected based on PD-L1 expression, pembrolizumab combined with chemotherapy as a first-line treatment demonstrated the greatest PFS benefit compared to the standard of care (SOC) (HR=0.92, 95% CI: 0.77-1.10). Among patients with R/M HNSCC, pembrolizumab combined with chemotherapy as a firstline treatment was the only immunotherapy regimen to show a PFS benefit compared to SOC (HR = 0.92, 95% CI: 0.77-1.10); however, the difference was not statistically significant.Meanwhile, nivolumab provided the most pronounced OS benefitadvantage (HR=0.71,95%CI:0.52-0.98). Additionally, pembrolizumab exhibited the most favorable safety profile relative to SOC (OR=0.12, 95% CI: 0.05-0.29). In second-line therapy, nivolumab outperformed SOC in multiple aspects, including OS (HR=0.68, 95% CI: 0.54-0.86), PFS (HR=0.87, 95% CI: 0.68-1.11), ORR (OR=0.40, 95% CI: 0.17-0.95), and grade ≥3 adverse events (OR=0.32, 95% CI: 0.19-0.54).Subgroup analysis by PD-L1 expression revealedindicated that nivolumab, compared to SOC, conferred the greatest OS benefit (HR=0.59, 95% CI: 0.34-1.00) as a first-line therapy in patients with PD-L1 expression ≥1%, while pembrolizumab combined with chemotherapy(pem-chemo) showed the most substantial PFS benefit (HR=0.82, 95% CI: 0.67-1.00). For patients with PD-L1 expression ≥20%, pem-chemo delivered the optimal OS (HR=0.60, 95% CI: 0.44-0.81) and PFS (HR=0.73, 95% CI: 0.55-0.97) outcomes compared to SOC.