Abstract B037: Incidence of General Systemic Adverse Events in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials
Authors: Jones Daniel T , Nanda Rishi K , Khalid Taimur , Aboaid Hazem , Ta Jason , Srinivasmurthy Ramaditya , Do Kenny , Nguyen Kevin , Fama Karina , Aamer Sarah , Myat Yin M , Bigcas Jo-Lawrence , Thein Kyaw Z 
Published: February 2025

Background: Head and neck squamous cell carcinoma (HNSCC), the most common head and neck malignancy, carries significant morbidity and mortality worldwide. Traditional treatments like cisplatin, cetuximab, and 5-fluorouracil are effective but often limited by toxicity and suboptimal long-term outcomes. Immune checkpoint inhibitors (ICIs), which enhance anti-tumor immunity, have recently emerged as promising therapies in locally advanced (LA) HNSCC. This study aims to assess the risk of systemic adverse events (AEs) in patients with LA HNSCC treated with the combination of immunotherapy and radiation compared to the standard of care. Methods: We conducted a comprehensive literature search using MEDLINE and EMBASE databases from inception through November 16th, 2024. Phase III randomized controlled trials (RCTs) utilizing ICIs in LA HNSCC reporting systemic AEs were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed using Cochran's Q-statistic. Fixed effects model was employed. Results: A total of 1,674 patients from three Phase III RCTs (KEYNOTE-412: n=796; JAVELIN Head and Neck 100: n=692; NRG-HN004: n=186) were included in this meta-analysis. The KEYNOTE-412 and JAVELIN trials compared ICIs (avelumab or pembrolizumab) plus chemoradiotherapy (CRT) to CRT alone, while NRG-HN004 evaluated radiotherapy with concurrent and adjuvant durvalumab versus cetuximab. The ICI arm demonstrated a higher incidence of adverse events, including any-grade anemia (53.29% vs. 49.56%, RR 1.10; 95% CI 1.00–1.21, P=0.05), high-grade nausea (7.05% vs. 4.73%, RR 1.55; 95% CI 1.05–2.30, P=0.03), any-grade pyrexia (14.80% vs. 9.34%, RR 1.64; 95% CI 1.26–2.14, P=0.0003), and any-grade hypothyroidism (19.65% vs. 12.20%, RR 1.61; 95% CI 1.28–2.03, P=0.0001). Hepatotoxicity was also elevated in the ICI arm, with higher rates of any-grade increased AST (14.34% vs. 8.47%, RR 1.65; 95% CI 1.25–2.18, P=0.0004), high-grade increased AST (1.85% vs. 0.62%, RR 2.66; 95% CI 1.00–7.07, P=0.05), and both any and high-grade increased ALT (16.65% vs. 11.21%, RR 1.51; 95% CI 1.18–1.93, P=0.001; and 2.66% vs. 1.12%, RR 2.31; 95% CI 1.09–4.92, P=0.03), respectively. There was no statistically significant difference between the two arms in terms of the incidence of any-grade nausea, high-grade anemia, any or high-grade vomiting, fatigue, decreased appetite, reduced white blood cell count, decreased neutrophil count, thrombocytopenia, hypomagnesemia, high-grade pyrexia, or deaths and serious adverse events attributed to treatment-related AEs. Conclusions: This study showed that patients with LA HNSCC treated with a combination of radiation and ICI compared to the standard of care have a higher risk of anemia, nausea, pyrexia, hypothyroidism, and hepatotoxicity. Early detection and effective management of these treatment-related AEs is essential to optimize the patients’ outcomes and maintain their quality of life.

Citation Format: Daniel T Jones, Rishi K Nanda, Taimur Khalid, Hazem Aboaid, Jason Ta, Ramaditya Srinivasmurthy, Kenny Do, Kevin Nguyen, Karina Fama, Sarah Aamer, Yin M Myat, Jo-Lawrence Bigcas, Kyaw Z Thein. Incidence of General Systemic Adverse Events in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B037.