Li Zhuoyang, Xie Yuxuan, Wang Tianhong, Liu Yuwei, Tian Yining, Hua Yusi
School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China.
Front Immunol. 2025 Sep 1;16:1631273. doi: 10.3389/fimmu.2025.1631273. eCollection 2025.
As one of the therapeutic modalities for treating tumors, immune checkpoint inhibitors (ICIs) have gained widespread application in clinical practice, including non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, and other types of cancers. However, the safety profile of combining ICIs remains inadequately understood, which poses limitations on the clinical utilization of this novel class of medications. To investigate the toxicity spectrum associated with combination immunotherapy, we conducted an extensive data mining and analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.
By mining adverse event (AE) reports from the FAERS database covering the period from the first quarter of 2011 through the second quarter of 2024, baseline data were analyzed using Cramer's V coefficient and p-value. Subsequently, two methods, the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network, were employed to detect AE signals for single immune checkpoint inhibitors (sICIs) and dual immunotherapy group (tremelimumab plus durvalumab and ipilimumab plus nivolumab, DIG).
A total of 55,052 patients and 118,001 AEs were selected. The DIG exhibited a higher incidence of AE signals across 14 distinct system organ class level. Moreover, DIG exhibited higher positive signal intensity compared to sICIs in the following preferred terms: myocarditis [ROR 2.221, 95% confidence interval lower limit of information component (IC) 0.486], immune-mediated myocarditis (ROR 2.922, IC 0.610), adrenal insufficiency (ROR 2.503, IC 0.602), hyperthyroidism (ROR 1.872, IC 0.305), thyroiditis (ROR 2.669, IC 0.546), immune-mediated enterocolitis (ROR 3.948, IC 0.937), pyrexia (ROR 1.570, IC 0.290), hepatic function abnormality (ROR 2.582, IC 0.591), hepatitis (ROR 2.705, IC 0.637), liver disorder (ROR 2.718, IC 0.646), immune-mediated hepatitis (ROR 5.504, IC 0.994), immune-mediated liver disorder (ROR 5.322, IC 0.966), cytokine release syndrome (ROR 7.650, IC 1.103), autoimmune diseases (ROR 1.754, IC 0.275), sepsis (ROR 1.414, IC 0.062), diabetic ketoacidosis (ROR 2.294, IC 0.472), type 1 diabetes mellitus (ROR 2.421, IC 0.508), arthritis (ROR 1.562, IC 0.113), myositis (ROR 2.204, IC 0.412), and acute kidney injury (ROR 1.708, IC 0.264).
Our findings indicate that the AEs associated with dual ICI predominantly originate from immune-related AEs, including myotoxicity, endocrine toxicity, and hepatotoxicity. Notably, cytokine release syndrome, a rarely reported AE with a strongly positive signal, warrants particular attention in clinical decision-making.
作为治疗肿瘤的方法之一，免疫检查点抑制剂（ICIs）在临床实践中已得到广泛应用，包括非小细胞肺癌、黑色素瘤、头颈部鳞状细胞癌、肝细胞癌及其他类型的癌症。然而，联合使用ICIs的安全性仍未得到充分了解，这限制了这类新型药物的临床应用。为了研究联合免疫治疗相关的毒性谱，我们对美国食品药品监督管理局不良事件报告系统（FAERS）数据库进行了广泛的数据挖掘和分析。
通过挖掘FAERS数据库中2011年第一季度至2024年第二季度期间的不良事件（AE）报告，使用克莱默V系数和p值分析基线数据。随后，采用两种方法，即报告比值比（ROR）和贝叶斯置信传播神经网络，来检测单一免疫检查点抑制剂（sICIs）和双重免疫治疗组（曲美木单抗加度伐利尤单抗以及伊匹木单抗加纳武单抗，DIG）的AE信号。
共选取了55,052名患者和118,001起AE事件。DIG在14个不同的系统器官分类水平上表现出更高的AE信号发生率。此外，在以下首选术语中，DIG与sICIs相比表现出更高的阳性信号强度：心肌炎[ROR 2.221，95%置信区间信息成分（IC）下限0.486]、免疫介导的心肌炎（ROR 2.922，IC 0.610）、肾上腺功能不全（ROR 2.503，IC 0.602）、甲状腺功能亢进（ROR 1.872，IC 0.305）、甲状腺炎（ROR 2.669，IC 0.546）、免疫介导的小肠结肠炎（ROR 3.948，IC 0.937）、发热（ROR 1.570，IC 0.290）、肝功能异常（ROR 2.582，IC 0.591）、肝炎（ROR 2.705，IC 0.637）、肝脏疾病（ROR 2.718，IC 0.646）、免疫介导的肝炎（ROR 5.504，IC 0.994）、免疫介导的肝脏疾病（ROR 5.322，IC 0.966）、细胞因子释放综合征（ROR 7.650，IC 1.103）、自身免疫性疾病（ROR 1.754，IC 0.275）、脓毒症（ROR 1.414，IC 0.062）、糖尿病酮症酸中毒（ROR 2.294，IC 0.472）、1型糖尿病（ROR 2.421，IC 0.508）、关节炎（ROR 1.562，IC 0.113）、肌炎（ROR 2.204，IC 0.412）和急性肾损伤（ROR 1.708，IC 0.264）。
我们的研究结果表明，与双重ICI相关的AE主要源于免疫相关AE，包括肌毒性、内分泌毒性和肝毒性。值得注意的是，细胞因子释放综合征是一种报告较少但信号强烈阳性的AE，在临床决策中值得特别关注。
