The impact of surgery and the type of immune check point inhibitors (ICI) in patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC) receiving immunotherapy: An updated systematic review and meta-analysis of randomized controlled trials.

Abstract

e18081 Background: Locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains a clinical challenge with high recurrence rates despite standard-of-care definitive or perioperative therapy. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent or metastatic disease, their efficacy in the curative-intent setting for LA HNSCC is less clear. This meta-analysis evaluates the efficacy of ICIs in this setting, specifically examining the impact of surgical intervention and the distinct roles of PD-1 versus PD-L1 blockade. Methods: A systematic search of MEDLINE and EMBASE was conducted through January 10, 2026, to identify Phase II and III randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors (ICIs) in locally advanced head and neck squamous cell carcinoma (LA HNSCC). Clinical trials also covered both definitive (non-surgical) and perioperative (surgical) settings. To explore biological drivers of efficacy, trials were stratified by ICI target: PD-1 inhibitors (Pembrolizumab, Nivolumab) and PD-L1 inhibitors (Avelumab, Durvalumab, Atezolizumab). The primary endpoints were progression-free survival (PFS), event-free survival (EFS) or disease-free survival (DFS). Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects inverse variance model. Study heterogeneity was evaluated using Cochran’s Q and the I² statistic. Results: A total of seven trials (n=3605), one phase II (GORTEC 2015-01 PembroRad) and six phase III (NRG-HN004, KEYNOTE-412, NIVOPOSTOP, JAVELIN Head and Neck 100, KEYNOTE-689, and IMvoke010) were included in the primary analysis. In the overall cohort, adding ICIs did not significantly improve PFS, EFS, or DFS (HR 0.90; 95% CI, 0.77–1.06; p=0.20) or OS (HR 0.95; 95% CI, 0.80–1.14; p=0.59). However, significant differences emerged upon segregation. A significant PFS benefit was observed in the perioperative/surgical group (HR 0.75; 95% CI, 0.64–0.88; p=0.0003), but not in the definitive/non-surgical group (HR 1.01; 95% CI, 0.84–1.22; p=0.89). PD-1 inhibitors significantly improved PFS (HR 0.78; 95% CI, 0.69–0.89; p=0.0001). PD-L1 inhibitors provided no significant benefit (HR 1.12; 95% CI, 0.92–1.36; p=0.26). Conclusions: The addition of ICIs to standard therapy for LA HNSCC does not provide a universal survival benefit. The therapeutic efficacy of ICIs in this setting appears to be restricted to patients undergoing surgical resection and those treated with PD-1 rather than PD-L1 inhibitors. Further research is required to refine patient selection and optimize treatment sequences for high-risk LA HNSCC populations.