Zhongji Chen, Zhong Zhong, Weiming Liang, Qiwen Feng, Minyao Wu, 林麗黛, Guanlan Huang, Xiaoxia Tang, Jieru Quan, Jiayong Wei, Jiongying Qin
Introduction This meta-analysis was designed to compare the efficacy and safety of PD-1/PD-L1 inhibitors versus chemotherapy or cetuximab in the treatment of platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Materials and Methods Four databases (PubMed, Embase, Web of Science, and Cochrane Library) were searched for RCTs comparing PD-1/PD-L1 inhibitors versus chemotherapy or cetuximab in the treatment of platinum-refractory R/M HNSCC, from the database’s establishment to 2 January 2026. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (trAEs) were subjected to meta-analyses. Results Five RCTs were included in the meta-analysis. The meta-analysis included a group of 1,700 patients diagnosed with platinum-refractory R/M HNSCC. Within this cohort, 926 patients were administered PD-1/PD-L1 inhibitors, while 774 patients received chemotherapy or cetuximab. Compared with chemotherapy or cetuximab, PD-1/PD-L1 inhibitors yielded superior OS (HR: 0.80, 95% CI: 0.72 to 0.89, P < 0.01), lower incidence of grade 3–5 trAEs (RR: 0.37, 95% CI: 0.30 to 0.45, P < 0.01) and any grade trAEs (RR = 0.74, 95% CI: 0.69 to 0.79, P < 0.01). There was no statistically significant difference in the ORR (RR: 1.01, 95% CI: 0.71 to 1.51, P = 0.94) or PFS (HR: 1.00, 95% CI: 0.90 to 1.11, P = 0.99) between the two groups. Conclusion The results indicated that PD-1/PD-L1 inhibitors were effective for platinum-refractory R/M HNSCC particularly in populations with high PD-L1 expression and exhibited a superior safety profile compared to chemotherapy or cetuximab. Additional well designed RCTs are required in the future to validate our conclusion. Clinical Trial Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251020053 , identifier PROSPERO (CRD420251020053).