Adjuvant Immune Checkpoint Inhibitors in Head and Neck Cancer: A Meta‐Analysis of Phase III Trials

ABSTRACT Background This meta‐analysis evaluates the efficacy and safety of adjuvant immune checkpoint inhibitors (ICIs), specifically nivolumab and pembrolizumab, when combined with standard chemoradiotherapy (CRT) in patients with resected locally advanced head and neck squamous cell carcinoma (LA‐HNSCC). Despite the potential of ICIs in improving survival outcomes, variability in patient responses and adverse event profiles remains a challenge. Methods Data were pooled from two Phase III randomized controlled trials, NIVOPOSTOP and KEYNOTE‐689, involving 1394 high‐risk patients with advanced disease, positive surgical margins, and extranodal extension. The primary endpoints were disease‐free survival (DFS) and overall survival (OS). Secondary endpoints included treatment‐related adverse events. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated for survival outcomes, and risk ratios (RR) for adverse events. Subgroup analyzes were performed based on PD‐L1 expression. Results The addition of ICIs to CRT resulted in significant improvements in DFS (HR: 0.75, 95% CI: 0.65–0.87) and OS (HR: 0.74, 95% CI: 0.65–0.85), representing a 25% reduction in the risk of recurrence and a 26% reduction in the risk of death. Subgroup analysis showed a greater benefit for patients with PD‐L1 expression (CPS ≥ 1), with a pooled HR of 0.66 (95% CI: 0.49–0.88). Adverse events were more frequent with ICIs, with 81% of patients reporting any‐grade adverse events and 42.9%–44.6% experiencing Grade 3 or higher events. The incidence of immune‐related adverse events was significantly higher in the immunotherapy groups ( p = 0.008), with notable increases in hypothyroidism and immune‐mediated toxicities. Treatment discontinuation due to adverse events occurred in 12.4%–17.7% of patients. Conclusions Adjuvant ICIs significantly improve survival outcomes in high‐risk patients with resected LA‐HNSCC, especially in case of CPS ≥ 1, but are associated with an increased risk of adverse events, particularly immune‐related toxicities. These findings support the integration of ICIs into postsurgical treatment regimens, though careful patient selection and monitoring are essential. Further research is needed to optimize treatment regimens and manage toxicities effectively.