Immune-related adverse events in older adults: Data mining of the FDA Adverse Event Reporting System

IntroductionRecent studies reveal that there is no difference in the efficacy of immune checkpoint inhibitors (ICIs) between younger adults and older adults. However, it remains unclear whether age is a risk factor for immune-related adverse events (irAEs).Materials and methodsTo analyze the association between irAEs and age based on data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database between January 2004 and December 2020, we performed a case/noncase study on ICI-related adverse events. Cases were defined as adverse event cases with ICI therapy and irAEs, and noncases were defined as adverse event cases with ICI therapy and without irAEs. One case was matched to a noncase using the sex, reporter, report year, and type of ICI regimen. The reporting odds ratios (RORs) were used to assess the disproportionality of irAEs between older adults (≥65 years) and younger adults (<65 years).ResultsThe study shows that compared with younger adults, the ROR of older adults was 1.12 (95% confidence interval [CI]: 1.08–1.16) and 1.18 (95% CI: 1.14–1.23) before and after matching, respectively. The signal of age-related irAEs was detected in patients treated with ICI monotherapy but not in patients treated with combination therapy. Further analysis revealed a spectrum of age-related toxicities including cardiovascular toxicities, lung toxicities, musculoskeletal toxicities, nervous system toxicities, renal toxicities, and skin toxicities.ConclusionIn this analysis performed based on the FAERS, irAE cases were more likely to be reported in older adults. Our pharmacovigilance study complements the safety data of clinical trials. Further studies are expected to explore the underlying reasons for irAEs in older adults.     

Immune Checkpoint Inhibitor Rechallenge Safety and Efficacy in Stage IV Non-Small Cell Lung Cancer Patients After Immune-Related Adverse Events

BackgroundDespite their anti-tumor efficacy, immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs). Grade ≥ 2 irAEs require ICI discontinuation. The decision to resume ICI treatment often remains challenging.MethodsWe retrospectively studied 1051 adult patients with stage IV non-small cell lung cancer (NSCLC) treated with ICIs at a single institution between January 2015 and December 2020, and identified 99 (9.4%) patients with grade≥2 irAEs necessitating treatment interruption. Forty patients underwent retreatment (rechallenged group), while 59 discontinued the treatment (discontinued group).ResultsBaseline characteristics of patients in the 2 groups were similar. Initial irAEs were less severe in the rechallenged group. After rechallenging, 24 of 40 (60%) patients had recurrence of the same or de-novo irAEs. Twenty (50%) developed second grade≥ 2 irAEs. No grade 4 irAE or irAE-related death occurred after rechallenging. Using multivariate analysis, no statistically significant differences in overall survival (OS) (HR: 1.10, 95% CI: 0.57-2.15, P = .77) or progression-free survival (PFS) (HR: 0.87, 95% CI: 0.45-1.71, P = .69) were noted between the 2 groups, while the best objective response prior to the initial irAEs was the only variable affecting OS and PFS.ConclusionsRechallenge was associated with a relative high risk of second grade≥ 2 irAEs. The risk was less if the initial irAEs were resolved. No differences were seen in survival outcomes of patients who had ICI rechallenge and those who did not. Permanent ICI discontinuation is an appropriate strategy after grade≥ 2 irAEs, especially severe irAEs.     

恶性肿瘤患者基于临床和血液学标记物的免疫检查点抑制剂相关不良事件预测模型的建立

  目的  本研究的目的是建立基于临床和血液学参数的免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）治疗的恶性肿瘤患者的免疫相关不良事件（immune-related adverse effects,irAEs）预测模型,如果经过验证,这些标记物的优点是易于整合到临床使用中,成本低廉。  方法  本研究是对2016年1月到2020年12月在天津医科大学肿瘤医院和山西白求恩医院接受至少一剂ICIs治疗的恶性肿瘤患者的回顾性研究。收集了基线特征、治疗细节和不良事件的数据。采用t检验、χ2检验和Logistic回归等方法确定影响因素,建立预测模型。  结果  任何级别和3级及以上的irAEs发生率分别为16.03%（76/474）和2.32%（11/474）,其中最常见的分别为内分泌毒性37.1%（39/105）和肺炎7.6%（8/105）。多因素分析显示,2线治疗irAEs发生的风险更大[比值比（Odds Ratio,OR）=3.302];球蛋白（OR=1.086）与irAEs的发生呈正相关,而直接胆红素（direct bilirubin,DBIL）（OR=0.723）与其呈负相关（Ｐ<0.05）。最终建立了基于“ICIs类型、治疗线数、球蛋白、DBIL和淋巴细胞/单核细胞比值（lymphocyte to monocyte ratio,LMR）”的预测模型,其受试者工作特征（receiver operating characteristic,ROC）曲线下面积（area under the curve,AUC）为0.775,95%CI:0.711～0.840,Ｐ<0.05,临界值为0.118,敏感度为92.5%,特异度为56.6%。  结论  基于ICIs类型、治疗线数、球蛋白、DBIL和LMR的预测模型对单纯接受ICIs的恶性肿瘤患者的irAEs预测效果较好,其中治疗线数、球蛋白和 DBIL是irAEs发生的独立预测因素。ICIs作为2线治疗以及治疗前高球蛋白和低DBIL 的人群发生irAEs的风险较高。      

Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients

ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3–4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.     

免疫检查点抑制剂治疗相关不良反应——新探索、新挑战

近年来,通过增强机体免疫系统对肿瘤细胞的杀伤作用,免疫检查点抑制剂(immune checkpoint inhibitor,ICI)在抗肿瘤治疗中的应用获得了显著的临床疗效.然而,多项证据表明,免疫治疗在激活免疫系统的同时可导致独特的免疫相关不良反应(immune-related adverse event,irAE)...     

免疫检查点抑制剂的心脏毒性及其机制

免疫检查点抑制剂（immune checkpoint inhibitor, ICI）的发展,推动了癌症治疗的革命性变化。ICI通过细胞免疫表面检查点（immune checkpoint）蛋白刺激免疫系统识别和破坏癌细胞。然而,使用ICI还可能在靶外器官（如心脏）中诱导免疫相关的不良事件（immune-related adverse events, irAE）。心脏损害的最常见表现是心肌炎,尽管罕见,但这些脱靶效应却可能危及生命。现有数据表明,ICI通过几种机制诱导其脱靶效应,包括直接结合正常组织中表达的细胞表面蛋白、激活与脱靶组织交叉反应的T细胞、产生自身抗体或增加前炎性细胞因子的水平。更好地了解癌症免疫治疗的不利影响及其潜在机制,将有助于开发生物标志,以识别有风险的患者和预防这些irAE的方法。     

免疫检查点抑制剂治疗相关静脉血栓栓塞症的研究进展

近年来,静脉血栓栓塞症(venous thromboembolism, VTE)已成为仅次于恶性肿瘤本身的第二位死亡原因。在精准治疗时代,既往标准癌症治疗手段已证实与VTE形成密切相关,如手术、化疗以及抗血管生成靶向治疗等。当代基于程序性死亡受体及其配体(programmed cell death 1 or its ligand, PD-1/PD-L1)或细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4,CTLA4)为治疗靶点的免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)的应用日趋成为常态并已成为指南推荐。然而,由ICIs诱导的各种非靶向自身免疫表现即免疫相关不良事件(immune-related adverse events, irAEs)不容忽视,其诱导的全身炎症对止血系统的影响迄今尚未得到适当研究。因此,临床医生非常有必要加强对ICIs相关VTE不良事件的认识。本文就ICIs相关VTE的发生率、危险因素、发病机制及临床管理原则等方面进行综述,以期为临床实践中免疫治疗相关静脉血栓的一级预防及精准治...     

免疫检查点抑制剂治疗尿路上皮癌的临床经验

  目的  探讨使用免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）治疗尿路上皮癌的临床有效性与安全性。  方法  回顾性分析2016年7月至2019年4月32例于辽宁省肿瘤医院使用ICIs治疗尿路上皮癌患者的临床资料。  结果  32例患者中4例完全缓解（complete remission,CR）、7例部分缓解（partial remission,PR）、5例疾病稳定（stable disease,SD）、9例疾病进展（progressiondisease,PD）、7例尚未评估。总客观有效率（overall response rate,ORR）为44.0%（11/25）,总疾病控制率（disease control rate,DCR）为64.0%（16/25）。至少经一种含铂类化疗失败患者的ORR为33.3%（5/15）,未经铂类化疗患者ORR达60.0%（6/10）。患者最多接受23个周期的ICIs治疗、约15个月,中位治疗周期为6个周期、约3.5个月。使用ICIs治疗患者通常耐受性良好,常见的免疫相关不良事件（immune-related adverse events,irAEs）为乏力、皮疹、甲减等。32例患者中5例出现irAEs,行静脉滴注皮质类固醇治疗。  结论  ICIs用于铂类化疗失败的局部晚期或转移性尿路上皮癌疗效明确,对于不能耐受或不愿意接受化疗的患者,或不适合手术的原发性尿路上皮癌患者,一线使用ICIs也是临床中可行的治疗方案,对irAEs需早期识别和给予持续治疗。      

Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint Inhibitors

The use of immune checkpoint inhibitor (ICI) therapy in the treatment of solid organ malignancies is becoming increasingly common. This has prompted the recognition of a new class of immune-related adverse effects (irAEs) stemming from the upregulation of T-cell activity causing autoimmunity. Neurological irAEs are a rare complication of ICIs that can lead to long-term morbidity. We report a rare case of encephalopathy after treatment with pembrolizumab, to which the patient achieved durable disease response despite discontinuation of therapy. We also review the pathophysiology, incidence, clinical presentation, diagnosis, and management of neurotoxicity secondary to ICIs. Treatment requires early administration of high-dose corticosteroids, and cessation of ICI therapy is often necessary after grade 3 or 4 irAEs. However, early data suggest that neurological irAEs correlate with a favorable disease response. Consideration should also be given to the optimal duration of ICI therapy to minimize the risk of toxicity and optimize health care expenditure.     

基于数据库分析免疫检查点抑制剂相关不良事件在中国人群中的现状

目的:描述中国人群中免疫检查点抑制剂（ICI）相关不良事件（AEs）的状况。方法:截止至2019年9月22日，检索PubMed、Web of Science和Embase数据库中所有ICI相关的临床试验，入组中国患者或主要是中国人群的试验将会被纳入本研究，汇总并比较治疗相关不良事件（TRAE）和免疫相关不良事件（irAE）的发生率。结果:纳入13个试验合计1 063例患者，其中922（86.7％）例接受ICI单药治疗，141（13.3％）例接受ICI联合化疗或抗血管生成治疗。在所有患者中，任意级别的TRAE、1-2级TRAE、3-5级TRAE、任意级别irAE、1-2级irAE、3-5级irAE的累计发生率分别为84.1％、63.3％、20.9％、43.3％、40.0％、3.0％；与ICI单药治疗相比，ICI联合化疗或抗血管治疗显著提高了3-5级TRAE（46.1％ vs 17.0％，P＜0.001）和3-5级irAE（7.1％ vs 2.0％，P=0.015）。通过比较不同ICI之间的毒性谱，我们发现了一些药物特异性不良反应。结论:ICI相关的不良事件一般为轻度，中国人群耐受性良好。但是，当ICI与化疗或抗血管治疗联合使用时，3-5级的TRAE和irAE会显著增加。     

免疫检查点抑制剂相关肺炎研究进展

随着癌症生物学和发病机制研究的不断深入,免疫检查点抑制剂（ICIs）得以问世,为晚期肿瘤患者带来了新的生存希望,从而开启了癌症免疫治疗的新时代,但随着免疫治疗在临床上的广泛应用,免疫相关不良事件（irAEs）也逐渐显现出来,并广泛为一线临床医师所熟知。免疫检查点抑制剂可激活T细胞攻击体内的正常组织和器官,并导致多种不良反应。而免疫检查点抑制剂相关肺炎（CIP）是irAEs中较为罕见且预后较差的并发症之一。本文参考目前国内外相关文献,就部分ICIs的治疗机制及CIP的发病率、危险因素、发生机制、临床表现、影像学表现与CIP的分级及治疗管理作一综述。     

The role of immunosuppressive agents in the management of severe and refractory immune‐related adverse events

The advent of immune checkpoint inhibitors has improved survival in some types of cancer and brought promising prospects to cancer immunotherapy. Despite their clinical benefits, significant off‐target toxicities resulting from the immune system activation have been observed, namely immune‐related adverse events (irAEs), which pose to clinicians a new challenge of optimal management. With steroids being the mainstay of current management of irAEs, immunosuppressive agents are especially indicated for severe or steroid‐refractory cases, based on current immunopathophysiological knowledge and on extrapolations of treatment options for primary autoimmune disorders. This review focuses on the status and recent clinical progress of immunosuppressive agents in the management of severe and steroid‐refractory irAEs.     

Pembrolizumab-Associated Cutaneous and Pulmonary Sarcoidosis in Non–Small Cell Lung Cancer Treatment

Immune checkpoint inhibitor (ICI) therapy has reshaped the treatment landscape in many cancers including non–small cell lung cancer (NSCLC). ICI-therapy can lead to a diverse array of immune-related adverse effects (irAEs), and prompt recognition and management are key to successful treatment. With wide-spread use of ICI therapy in clinical practice, rare irAEs are being increasingly recognized. This report documents a patient with advanced NSCLC who developed pembrolizumab-associated sarcoidosis with multiorgan involvement. Multidisciplinary management led to timely diagnosis and treatment, leading to improvement in symptoms. This case raises awareness of sarcoidosis as a rare side effect of pembrolizumab.     

Geriatric assessment and treatment outcomes in older adults with cancer receiving immune checkpoint inhibitors

ObjectivesImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but outcomes in older adults are not well defined. We evaluated the associations of geriatric assessment (GA) domains with treatment-related outcomes in older adults with solid tumors receiving ICIs.MethodsWe performed a single-center, retrospective study of patients age ≥65 years diagnosed with solid tumors who received ICIs and were evaluated with a GA from January 2011 to April 2017. Using Wilcoxon rank sum test, we examined the associations of GA domains and treatment-related outcomes, including the number of ICI cycles received, best response, immune-related adverse events (irAEs), and hospitalizations during ICI treatment.ResultsWe identified 28 patients (median age at ICI treatment = 78 years, range 66–93); 60% had Eastern Cooperative Oncology Group (ECOG) Performance Status of ≥2; 39% had lung cancer; 89% had stage IV cancer; and 50% received pembrolizumab. Seventy-five percent had at least one GA domain impairment. Patients with any instrumental activities of daily living (IADL) impairment received fewer cycles of ICI (median: 2.0 vs. 7.0 cycles, p = 0.02). In this small sample, neither age nor GA domain measures were associated with best response, irAEs, or hospitalization during ICI treatment.ConclusionsOlder adults treated with ICIs had a high prevalence of impairments in GA domains, and IADL impairments were associated with shorter duration of ICI treatment. Future prospective studies are needed to evaluate the role of the GA further in this vulnerable patient population in the immunotherapy era.     

免疫检查点抑制剂治疗中胃肠道毒副反应的管理

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）是一类新兴的抗肿瘤药物，它能极大程度的改善晚期癌症患者的临床预后，提高患者的生存率。ICIs通过阻断T细胞表面的共抑制受体来激活免疫系统，以发挥抗肿瘤的作用。但是在发挥其卓越治疗作用的同时，也可能会给患者带来许多不良反应，称为:免疫相关不良事件（immune-related adverse events，irAEs）。胃肠道毒性反应作为第二大高发的ICIs引发的irAEs，可对患者造成极其严重的影响，危重时甚至可导致患者死亡。ICIs诱导的胃肠道毒性反应种类繁多，最常见的反应为腹泻和胃肠道炎症。我们将重点了解ICIs类药物的作用机制、发生胃肠道毒性反应患者的临床症状及辅助检查结果，以便临床中及早的发现并诊断，方便管理与治疗。以期最大限度的在避免毒性反应的同时发挥ICIs的治疗作用。     

Incidence,Clinical Characteristics,and Predictors of Cardiovascular Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors

BackgroundCardiovascular immune-related adverse events (CV–irAEs) associated with immune checkpoint inhibitors (ICIs) may have been underreported given that most previous reports were retrospective. We aimed to evaluate the incidence, clinical characteristics, and predictors of CV–irAEs and determine the feasibility of serial cardiac monitoring using a combination of B-type natriuretic peptide, cardiac troponin T, and electrocardiogram for the prediction of future symptomatic (grade ≥2) CV–irAEs.Materials and MethodsThis was a prospective observational study that included 129 consecutive patients with non–small-cell lung cancer who received ICI monotherapy at a single center. Serial cardiac monitoring was performed during ICI monotherapy.ResultsA total of 35 (27%) patients developed any grade ≥1 CV–irAEs with a median time of onset of 72 (interquartile range 44-216) days after ICI treatment initiation. Multivariate Fine–Gray regression analysis showed that prior acute coronary syndrome (adjusted hazard ratio [HR] 3.15 (95% [CI], 2.03-4.91), prior heart failure hospitalization (adjusted HR 1.65 [95% CI, 1.17-2.33]), and achievement of disease control (adjusted HR 1.91, [95% CI, 1.16-3.14]) were significantly associated with grade ≥1 CV–irAEs. Serial cardiac monitoring revealed that patients with preceding grade 1 CV–irAEs were associated with a significantly higher risk of onset of grade ≥2 CV–irAEs compared with those without preceding grade 1 CV–irAEs (HR: 6.17 [95% CI, 2.97-12.83]).ConclusionCV–irAEs were more common than previously recognized and have several predictors. Moreover, serial cardiac monitoring may be feasible for the prediction of future grade ≥2 CV–irAEs.     

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab

BackgroundAnti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.Patients and methodsPatients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.ResultsOne hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.ConclusionsIn melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.     

免疫检查点抑制剂治疗非小细胞肺癌产生免疫相关不良反应和肺炎的特点及其危险因素分析

目的：探讨免疫检查点抑制剂(ICI)治疗非小细胞肺癌(NSCLC)产生的免疫相关不良反应(irAE)及ICI相关肺炎(ICI-P)的特点及其危险影响因素。方法：回顾性分析2019年1月到2021年12月间在山西白求恩医院胸部肿瘤科接受至少1次ICI治疗的114例NSCLC患者的一般性资料和临床特征的基线特征、治疗细节和发生irAE、ICI-P的数据,分析患者临床特征与irAE及ICI-P的关系,分析ICI-P发生的危险因素。观察ICI-P患者临床特点和治疗效果。结果：114例接受ICI治疗的NSCLC患者中有48例(42.11%)发生68次irAE,整体和严重irAE的发生率分别是59.65%、9.65%;从高到低排列发生率(仅列出前四位)：消化系统>呼吸系统>皮肤>内分泌系统;使用信迪利单抗>度伐利尤单抗>卡瑞利珠单抗=帕博利珠单抗;临床特征中的年龄与irAE发生有关联。15例患者发生ICI-P,整体发生率为13.16%,占irAE患者的31.25%,其中4例为重症,占irAE数的8.33%、ICI-P数的26.66%;发生于联合治疗的多于单药治疗(73...