Evaluation of neoadjuvant immunotherapy regimens for head and neck squamous cell carcinoma: a systematic review and single-arm and network meta-analysis

BACKGROUND: Although multiple neoadjuvant immunotherapy (NAI) regimens have been explored in head and neck squamous cell carcinoma (HNSCC) recently, the optimal selection remains largely debatable. The present study aimed to comparatively evaluate clinical outcomes across various NAI regimens in resectable HNSCC. METHODS: We systematically searched studies published from 2000 to June 2025. Data encompassing treatment efficacy (objective response rate [ORR], pathological complete response [pCR], major pathological response [MPR], tumor downstaging), survival outcomes (overall survival [OS], disease-free survival [DFS]), and safety profiles (grade ≥3 immune-related adverse events [irAEs]) were pooled and analyzed from eligible studies. Subsequently, network meta-analysis (NMA) with surface under the cumulative ranking curve (SUCRA) was implemented to comparatively evaluate therapeutic regimens across studies. RESULTS: A total of 44 studies (7 randomized controlled trials and 39 single-arm trials) involving 1688 patients were included. Pooled analysis revealed superior treatment response with neoadjuvant immunochemotherapy (NIC) versus alternative regimens: ORR = 80% (0.70-0.88), pCR = 40% (0.35-0.44), MPR = 64% (0.59-0.69), and pathological downstaging = 79% (0.71-0.86), complemented by favorable survival (2-year OS = 91% [0.86-0.94]; 2-year DFS = 90% [0.83-0.94]). NMA of 7 RCTs demonstrated that NIC conferred significant improvements in pCR and downstaging rates compared to mono-immunotherapy, immune-targeted therapy, and dual-immunotherapy. Additionally, NIC trended toward better ORR, MPR, and 2-year DFS, though the differences failed to attain statistical significance. SUCRA analysis consistently ranked NIC highest across all evaluated efficacy endpoints. Notably, while SUCRA analysis ranked NIC highest for irAE risk, NMA revealed no significant differences in the incidence rates across regimens. CONCLUSIONS: Our findings establish NIC as the superior regimen within immunotherapy-based neoadjuvant modalities for achieving pCR and tumor downstaging in HNSCC patients, thereby providing robust evidence to support its clinical prioritization and assist in treatment decision-making. Nevertheless, high-quality trials are needed to further compare various NAI regimens as well as NAI against neoadjuvant chemotherapy to conclude the optimal treatment strategy.