e24179 Background: Immune checkpoint inhibitors (ICIs) have improved outcomes in recurrent and metastatic head and neck squamous cell carcinoma (HNSCC). In the locally advanced, curative-intent setting, however, their safety profile is less well defined. Several randomized trials have evaluated the addition of ICIs to standard treatment strategies for locally advanced HNSCC (LA HNSCC), but concerns regarding treatment-related toxicity remain. We conducted an updated systematic review and meta-analysis to better characterize adverse events associated with ICI-based approaches in LA HNSCC. Methods: MEDLINE and EMBASE were searched through January 10, 2026 to identify phase II and III randomized trials evaluating ICIs in LA HNSCC. Eligible studies compared ICI-containing regimens with standard-of-care therapy. Safety endpoints included treatment-related adverse events (TRAEs), serious adverse events, adverse events of special interest (AESI), immune-mediated adverse events, and treatment-related mortality. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects inverse-variance model. Results: Seven randomized trials comprising 3,605 patients were included. Overall, the addition of ICIs did not meaningfully change the rate of treatment-related adverse events, either for events of any grade (RR 1.01, 95% CI 0.97 to 1.04; p = 0.69) or for high-grade toxicity (RR 1.06, 95% CI 0.98 to 1.13; p = 0.12). Serious adverse events were observed more often in ICI-containing arms (RR 1.28, 95% CI 1.11 to 1.47; p = 0.0005), though deaths attributed to treatment-related toxicity were uncommon and similar between groups (RR 1.11, 95% CI 0.56 to 2.20; p = 0.77). Events categorized as AESI were also more frequent with ICI use (RR 1.86, 95% CI 1.23 to 2.79; p = 0.003). As anticipated, immune-mediated toxicity occurred more often with ICIs. Both any-grade immune-related adverse events (RR 1.91, 95% CI 1.30 to 2.81; p = 0.001) and high-grade immune-related adverse events (RR 3.93, 95% CI 2.07 to 7.48; p < 0.001) were increased. Hypothyroidism was limited to low-grade events but occurred more frequently among ICI-treated patients (RR 2.50, 95% CI 1.53 to 3.83; p < 0.001). In contrast, locoregional toxicities such as stomatitis, radiation-associated skin injury, dysphagia, xerostomia, and dysgeusia were similar across treatment arms. Conclusions: Across randomized trials, ICI-based strategies in LA HNSCC were associated with higher rates of immune-mediated adverse events, most of which were low grade. Importantly, this did not translate into higher overall or high-grade treatment-related toxicity or increased treatment-related mortality. Locoregional toxicity patterns remained comparable, supporting continued evaluation of ICIs in curative-intent treatment settings with appropriate toxicity monitoring.
Nanda et al. (Thu,) studied this question.