Abstract C057: Locoregional toxicities associated with immunotherapy plus chemoradiation in locally advanced head and neck cancer: A meta-analysis of phase 3 trials

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck and ranks seventh among all cancers worldwide. Standard chemoradiotherapy (CRT) traditionally includes cisplatin and 5-fluorouracil. The FDA approval of pembrolizumab in 2019 for recurrent/metastatic HNSCC has prompted investigation into immune checkpoint inhibitors (ICIs) for the treatment of locally advanced (LA) HNSCC. As ICIs are integrated into curative-intent regimens, evaluating associated locoregional toxicities is essential. This meta-analysis assesses the incidence of locoregional adverse events (AEs) associated with adding ICIs to standard CRT in LA HNSCC. Methods: A comprehensive literature search of MEDLINE and EMBASE was conducted through July 10, 2025. Eligible studies included phase III randomized controlled trials (RCTs) evaluating ICIs in LA HNSCC and reporting locoregional AEs. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method. Heterogeneity was assessed using Cochran’s Q-statistic. A fixed-effects model was applied. Results: Two phase III RCTs were included (KEYNOTE-412, n=796; JAVELIN Head and Neck 100, n=692), totaling 1,488 patients. Both trials compared ICIs (avelumab or pembrolizumab) plus CRT versus CRT alone. The incidence of high-grade odynophagia was significantly higher in the ICI group (4.83%) compared to control (2.29%; RR 2.11; 95% CI: 1.20–3.72; p=0.010). No statistically significant differences were observed in the rates of other locoregional AEs, including any-grade or high-grade stomatitis, radiation dermatitis, xerostomia, dysphagia, dysgeusia, oropharyngeal pain, tinnitus, or any-grade odynophagia. Conclusion: The addition of ICIs to standard CRT in LA HNSCC appears to have a comparable locoregional toxicity profile to CRT alone, except for an increased risk of high-grade odynophagia. These findings suggest that ICI-based intensification may be safely considered in selected patients, with attention to managing odynophagia-related symptoms during treatment. Citation Format: Ramaditya Srinivasmurthy, Jason Ta, Daniel T. Jones, Riccesha Hattin, Rishi K. Nanda, Taimur Khalid, Abbas Hussain, Kenny Do, Sisi Tian, Jo-Lawrence Bigcas, Kyaw Z. Thein. Locoregional toxicities associated with immunotherapy plus chemoradiation in locally advanced head and neck cancer: A meta-analysis of phase 3 trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C057.