Immunotherapy plus targeted therapy for recurrent or metastatic head and neck squamous cell carcinoma: an updated meta-analysis and subgroup analysis by target mechanism.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with dismal outcomes for patients with recurrent or metastatic (R/M) disease. Although immune checkpoint inhibitors (ICIs) have reshaped the treatment paradigm for R/M HNSCC, the efficacy of monotherapy remains limited. This meta-analysis was performed to comprehensively evaluate the efficacy and safety of immunotherapy combined with targeted therapy for R/M HNSCC and to clarify sources of between-study heterogeneity. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science from inception to May 1, 2026. Eligible studies enrolled patients with histologically confirmed R/M HNSCC receiving immunotherapy combined with targeted therapy and reported predefined efficacy or safety endpoints. Pooled analyses were conducted using Review Manager 5.4 to estimate rates of complete response (CR), partial response (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), and grade ≥3 treatment-related adverse events (TRAEs). Subgroup analyses stratified by targeted therapy mechanism were performed to explore heterogeneity. RESULTS: A total of 22 studies comprising 1118 patients were included. Pooled estimates were as follows: CR rate 0.08 (95% CI: 0.05-0.10), PR rate 0.35 (95% CI: 0.27-0.42), ORR 0.41 (95% CI: 0.32-0.49), SD rate 0.26 (95% CI: 0.22-0.30), DCR 0.75 (95% CI: 0.66-0.83), median PFS 6.9 months, median OS 14.8 months, and grade ≥3 TRAEs rate 0.37 (95% CI: 0.24-0.50). Significant heterogeneity was detected across most endpoints and could not be alleviated by sensitivity analysis. Subgroup analyses demonstrated that anti-EGFR combinations achieved the highest ORR and DCR, whereas novel targeted combinations exhibited a more favorable safety profile. CONCLUSIONS: Immunotherapy combined with targeted therapy yields promising efficacy and manageable toxicity in patients with R/M HNSCC. The type of targeted agent represents a major source of heterogeneity. Anti-EGFR plus immunotherapy regimens show robust antitumor activity, while novel targeted combinations exhibit better tolerability. These findings support mechanism-based individualized combination strategies for R/M HNSCC in clinical practice. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251050561.