Efficacy and Safety of TKI Plus PD-1/PD-L1 Versus Monotherapy in Advanced HNSCC: A Systematic Review and Meta-Analysis.

Abstract

PD-1/PD-L1 inhibitors are standard therapy for advanced head and neck squamous cell carcinoma (HNSCC), but benefit only a subset of patients. Combining tyrosine kinase inhibitors (TKIs) with immunotherapy may improve outcomes. Following PRISMA 2020, PubMed, Embase, Cochrane Library and Web of Science were searched through January 2026 for clinical trials of PD-1/PD-L1 inhibitor monotherapy or TKI combination therapy in advanced HNSCC. Primary and secondary outcomes were objective response rate (ORR), 1-year overall survival (OS), median OS, progression-free survival (PFS) and safety. Random-effects meta-analyses, risk-of-bias assessment and GRADE evaluation were performed. Eleven trials including 1190 patients were analysed. Combination therapy achieved a higher pooled ORR than monotherapy (36.2% vs. 16.6%; odds ratio 2.79, 95% CI 1.89-4.12; p < 0.001). The pooled 1-year OS rate was also higher with combination therapy (63.8% vs. 37.8%). Median PFS ranged from 3.2 to 14.6 months with combination therapy and 1.8-3.0 months with monotherapy. Grade ≥ 3 adverse events, including hypertension, proteinuria and hand-foot syndrome, were more frequent but manageable. TKI plus PD-1/PD-L1 inhibition improves tumour response and may prolong survival, although evidence is limited by small early-phase studies, heterogeneity and cross-trial confounding. PROSPERO CRD1297918.