Background: Real-world safety profiles of immune checkpoint inhibitors (ICIs) in older adults remain insufficiently characterized. Although ICIs are widely used across tumor types, older patients, particularly those with frailty, multimorbidity, or polypharmacy, are consistently under-represented in clinical trials, limiting the external validity of trial-derived toxicity estimates. Robust real-world data are therefore essential to clarify the incidence, seriousness, and age-related patterns of immune-related adverse events (irAEs) in routine practice.Methods: This is a nationwide retrospective study of spontaneous ICI-related ADRs reported in INFARMED’s Portal RAM (2011–2024). We evaluated the frequency, seriousness, fatality, and organ-specific patterns of ICI-related adverse drug reactions (ADRs) reported to the Portuguese National Pharmacovigilance System. The analytic unit was the ADR case. Endpoints included seriousness (primary), fatality, hospitalization, time-to-onset, and System Organ Class. Multivariable logistic regression adjusted for age, sex, regimen, tumor type, polypharmacy, and calendar period; sensitivity analyses using first ADR per patient were concordant.Results: We identified 2300 eligible ICI-related ADRs (corresponding to 925 patients). Median age at the time of ADR was 65 years (IQR not reported); 33.7% occurred in adults aged ≥70 years, and 62.8% of reports involved male patients. PD-1 inhibitors accounted for 77.5% of ADRs, and monotherapy for 72.9%. Overall, 85.8% of ADRs were classified as serious; 17.9% led to hospitalization and 19.1% were fatal. Serious-event reporting was similar in older and younger adults (≥70 vs. <70 years: 84.5% vs. 86.5%,p= 0.22), and the proportion explicitly labeled immune-related did not differ (9.3% vs. 8.7%,p= 0.56). In contrast, fatal outcomes were significantly more common in older adults (25.3% vs. 16.0%;p< 0.001). Age was associated with distinct organ-specific patterns. Adults ≥ 70 years had higher odds of nervous system disorders (aOR 1.75, 95% CI 1.23–2.48) and immune system disorders (aOR 1.42, 95% CI 1.02–1.98), but lower odds of hepatobiliary (aOR 0.52, 95% CI 0.36–0.76;p= 0.001) and blood/lymphatic disorders (aOR 0.50, 95% CI 0.32–0.79). In multivariable models, age ≥ 70 years did not predict seriousness (aOR 0.98, 95% CI 0.76–1.27), whereas combination therapy remained independently associated with increased seriousness (aOR 1.57, 95% CI 1.13–2.18). Conversely, age ≥ 70 years independently predicted fatal outcomes (aOR 1.66, 95% CI 1.31–2.09). Later calendar periods (2017–2024) were associated with substantially lower fatality (aOR 0.16; 95% CI 0.10–0.27). CTLA-4-containing regimens demonstrated a tendency toward higher fatality (aOR 1.50; 95% CI 0.94–2.37).Conclusions: Chronological age does not seem to increase the likelihood of reporting a serious ICI-related ADR, but, once toxicity occurs, older adults experience higher fatality rates. Age-related phenotypic differences and regimen-specific risks highlight the need for early recognition systems and tailored toxicity management in older populations.
背景：免疫检查点抑制剂（ICIs）在老年患者中的真实世界安全性特征仍未得到充分阐明。尽管ICIs广泛应用于多种肿瘤类型，但老年患者，特别是那些伴有衰弱、多病共存或多药联用的患者，在临床试验中代表性持续不足，这限制了试验得出的毒性评估结果的外部有效性。因此，需要可靠的真实世界数据来明确常规临床实践中免疫相关不良事件（irAEs）的发生率、严重程度以及与年龄相关的模式。 方法：这是一项基于INFARMED的Portal RAM系统（2011–2024年）自发报告的全国性回顾性研究。我们评估了向葡萄牙国家药物警戒系统报告的ICI相关药物不良反应（ADRs）的频率、严重性、致死性以及器官特异性模式。分析单元为ADR病例。终点指标包括严重性（主要）、致死性、住院率、发生时间以及系统器官分类。多变量逻辑回归模型校正了年龄、性别、治疗方案、肿瘤类型、多药联用和日历时期等因素；使用每位患者的首次ADR进行的敏感性分析结果一致。 结果：我们确定了2300例符合条件的ICI相关ADRs（对应925名患者）。发生ADR时的中位年龄为65岁（未报告IQR）；33.7%发生在≥70岁的成人中，62.8%的报告涉及男性患者。PD-1抑制剂占ADR的77.5%，单药治疗占72.9%。总体而言，85.8%的ADR被归类为严重；17.9%导致住院，19.1%为致死性。老年与年轻成人（≥70岁 vs. <70岁）的严重事件报告率相似（84.5% vs. 86.5%，p=0.22），明确标记为免疫相关的比例也无差异（9.3% vs. 8.7%，p=0.56）。相比之下，致死性结局在老年患者中显著更常见（25.3% vs. 16.0%；p<0.001）。年龄与不同的器官特异性模式相关。≥70岁的成人发生神经系统疾病（校正比值比[aOR] 1.75，95% CI 1.23–2.48）和免疫系统疾病（aOR 1.42，95% CI 1.02–1.98）的几率更高，但发生肝胆系统疾病（aOR 0.52，95% CI 0.36–0.76；p=0.001）和血液/淋巴系统疾病（aOR 0.50，95% CI 0.32–0.79）的几率较低。在多变量模型中，年龄≥70岁并不能预测严重性（aOR 0.98，95% CI 0.76–1.27），而联合治疗则与严重性增加独立相关（aOR 1.57，95% CI 1.13–2.18）。相反，年龄≥70岁可独立预测致死性结局（aOR 1.66，95% CI 1.31–2.09）。较晚的日历时期（2017–2024年）与致死率显著降低相关（aOR 0.16；95% CI 0.10–0.27）。含CTLA-4的治疗方案显示出更高的致死性趋势（aOR 1.50；95% CI 0.94–2.37）。 结论：时序年龄似乎并未增加报告严重ICI相关ADR的可能性，但一旦发生毒性反应，老年患者的致死率更高。与年龄相关的表型差异和特定治疗方案的风险凸显了在老年人群中建立早期识别系统和个体化毒性管理的必要性。
肿瘤(癌症)患者之家