Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland
Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland.
J Immunother Cancer. 2024 Nov 3;12(11):e009902. doi: 10.1136/jitc-2024-009902.
To date, evidence on late-onset immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is limited to a small number of clinical cases. This study aimed to identify drug- and patient-related characteristics potentially associated with the reporting of late-onset irAEs with ICIs in VigiBase, the WHO global database of individual case safety reports (ICSRs).
Observational study comparing deduplicated ICSRs with ICIs reporting late-onset irAEs (occurred >90 days after ICI discontinuation) versus ICSRs with ICIs not reporting late-onset irAEs, collected in VigiBase from 2011 to December 31, 2022. Logistic regression was used to model the relationship between drug-related and patient-related characteristics of ICSRs and the reporting of late-onset irAEs. Significance was determined for variables with the lower bound of the 95% CI of the reporting OR (ROR) higher than 1 and a p value <0.05.
The study population consisted of 6006 ICSRs with ICI-related irAEs (4574, 76.2%, originated from Europe; 3900, 64.9%, involved males; median patient age was 67 years, IQR 59-74 years). Of these, 344 (5.7%) ICSRs reported a total of 388 late-onset irAEs, among which the most frequent were thyroiditis (n=45), pneumonitis (n=37), interstitial lung disease (n=25), hepatitis (n=23) and vitiligo (n=19). Median time to onset since ICI discontinuation was 167 days (IQR 115-294 days), with negligible proportion (3.2%) of co-reported antineoplastic agents during the discontinuation period. Logistic regression models showed disproportionate reporting of late-onset irAEs with ICI combination therapy (ROR 2.33, 95% CI 1.19 to 4.57), reporting of multiple irAEs (ROR 3.96, 95% CI 2.85 to 5.52), reporting of cutaneous irAEs (ROR 1.83, 95% CI 1.24 to 2.71), and melanoma (ROR 1.47, 95% CI 1.04 to 2.06).
This global pharmacovigilance study provides the largest case series of late-onset irAEs with ICIs to date and identifies characteristics of ICSRs associated with disproportionate reporting. Dedicated prospective observational studies focused on long-term sequelae, quality of life and survival of patients developing late-onset irAEs with ICIs should be planned to confirm whether these reporting characteristics are predictors of actual occurrence. Furthermore, translational research should be encouraged to clarify the molecular mechanisms underlying late-onset irAE development.
迄今为止，免疫检查点抑制剂（ICI）相关迟发性免疫相关不良事件（irAE）的证据仅限于少数临床病例。本研究旨在通过世界卫生组织个体病例安全报告数据库（VigiBase），确定与 ICI 相关迟发性 irAE 报告相关的药物和患者特征，该数据库包含了来自 2011 年至 2022 年 12 月 31 日的个体病例安全报告。
本研究是一项观察性研究，比较了 VigiBase 中报告 ICI 相关迟发性 irAE（ICI 停药后 >90 天发生）的 ICSR 与未报告 ICI 相关迟发性 irAE 的 ICSR，使用逻辑回归模型来评估 ICSR 中的药物相关和患者相关特征与迟发性 irAE 报告之间的关系。报告比值比（ROR）的 95%置信区间下限高于 1 且 p 值 <0.05 的变量被认为具有统计学意义。
研究人群包括 6006 例 ICI 相关 irAE 的 ICSR（4574 例，占 76.2%，来自欧洲；3900 例，占 64.9%，涉及男性；中位患者年龄为 67 岁，IQR 59-74 岁）。其中 344 例（5.7%）ICSR 报告了总共 388 例迟发性 irAE，其中最常见的是甲状腺炎（n=45）、肺炎（n=37）、间质性肺病（n=25）、肝炎（n=23）和白癜风（n=19）。从 ICI 停药到发病的中位时间为 167 天（IQR 115-294 天），在停药期间报告了极少量的（3.2%）联合抗肿瘤药物。逻辑回归模型显示，ICI 联合治疗（ROR 2.33，95%CI 1.19-4.57）、报告多种 irAE（ROR 3.96，95%CI 2.85-5.52）、报告皮肤 irAE（ROR 1.83，95%CI 1.24-2.71）和黑色素瘤（ROR 1.47，95%CI 1.04-2.06）的报告与迟发性 irAE 具有不成比例的相关性。
这项全球药物警戒研究提供了迄今为止最大的 ICI 相关迟发性 irAE 病例系列，并确定了与不成比例报告相关的 ICSR 特征。应计划进行专门的前瞻性观察研究，以关注发生迟发性 irAE 的患者的长期后果、生活质量和生存情况，以确认这些报告特征是否是实际发生的预测因素。此外，应鼓励转化研究以阐明迟发性 irAE 发展的分子机制。
