Analysis of immune-related adverse events in gastrointestinal malignancy patients treated with immune checkpoint inhibitors

Immune checkpoint inhibitors are becoming an increasingly common treatment for advanced gastrointestinal cancer, but the possibility of immune-related adverse events has raised concerns. This study aimed to evaluate the risks of immune-related adverse events between patients who received immune checkpoint inhibitors and those who received chemotherapy among different types of gastrointestinal cancer. The study utilized data from the multicenter TriNetX database in the United States covering the period between 2015 and 2022. Hazard ratios and 95% confidence intervals were used to describe the relative hazard of immune-related adverse events based on comparing time-to-event rates. Our study revealed that the incidence of immune-related adverse events was significantly higher in patients who received immune checkpoint inhibitors and chemotherapy compared to those who received chemotherapy only in treating gastrointestinal cancer. CTLA-4 inhibitors tended to have a higher rate of immune-related adverse events compared to PD-1/PD-L1 inhibitors. Our study found a lower mortality rate among patients who developed immune-related adverse events compared to those who did not after propensity score matching (HR, 0.661; 95% CI 0.620–0.704; p < .01). We provide important real-world data on the incidence and impact of immune-related adverse events in patients with advanced gastrointestinal cancer treated with immune checkpoint inhibitors. Our study's results support clinicians in making informed decisions about the potential benefits and risks of immune checkpoint inhibitor therapy for patients with gastrointestinal cancer.     

Racial disparities in immune-related adverse events of immune checkpoint inhibitors and association with survival based on clinical and biochemical responses

BACKGROUNDImmune checkpoint inhibitors (ICPi) cause various immune-related adverse events (irAE) with thyroid dysfunction as a commonly reported abnormality. There is increasing evidence showing positive association with development of irAE and survival. However, prior trials with ICPi had underrepresentation of minorities with < 5% African Americans.AIMTo evaluate the association between development of irAE and survival outcomes among a racially diverse patient population.METHODSData on patients with stage IV solid malignancies treated with programmed cell death-protein 1/programmed death ligand 1 blockers between January 2013 and December 2018 across MedStar Georgetown Cancer Institute facilities were retrospectively reviewed. Patients treated with cytotoxic T-lymphocyte-associated protein 4 inhibitors were excluded. Progression free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using Kaplan-Meier methods and Wilcoxon rank sum test for comparison.RESULTSOut of 293 patients who met eligibility criteria, 91 pts (31%) had any grade irAE; most common AE were endocrine (40.7%) specifically TSH elevation, dermatological (23.1%) and rheumatologic (18.7%). Proportion of irAE was significantly higher in Caucasians vs African Americans (60.4% vs 30.8%), in patients with low programmed death ligand 1, lower LDH, older age, and those who had more treatment cycles with ICPi. Rate of progression was lower in patients with irAE (30.8% vs 46.0%, P = 0.0140). Median PFS (5.8 vs 3.0 mo, P = 0.0204) and OS (17.1 vs 7.2 mo, P < 0.0001) were higher with irAE. Statistically significant difference in OS (17.1 vs 8.6 mo, P = 0.0002) but not in PFS (5.8 vs 3.3 mo, P = 0.0545) was noted with endocrine irAE. No differences in survival were observed among other commonly reported irAE. Differences in survival among subgroups of patients with irAE are described.CONCLUSIONDevelopment of irAE positively correlated with improved PFS and OS as reported in previous studies. To our knowledge, this is the first study observing differences in OS favoring endocrine AE and Caucasian race. These factors may be potential surrogate markers of prognosis pending replication of these results in large-scale studies.     

Management of immune-related adverse events resulting from immune checkpoint blockade

Introduction: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient’s treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg.

Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs.

Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.     

真实世界中免疫检查点抑制剂导致免疫相关不良反应病例分析

目的:探讨免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）导致的免疫相关不良反应（immune-related adverse events,irAEs）的发生情况。方法:收集并分析2018年1月至2021年3月我院irAEs的具体情况,包括基本资料、用药情况、不良反应具体情况、治疗情况等。结果:63例irAEs,包括肺毒性3例、肝脏毒性9例、皮肤毒性23例、内分泌毒性15例、神经毒性4例、肾毒性3例、胃肠毒性1例、心脏毒性2例、血液毒性1例、眼毒性2例。男性47例,女性16例,中位发病年龄61岁,不良反应中位发生时间6.6周,17例需要大剂量糖皮质激素治疗。毒性级别1-2级49例,3-4级13例,5级1例。少见irAEs 14例,1例死于心肌炎。结论:irAEs涉及的器官或系统较多,多数在3级以下。常见不良反应预后较好。少见irAEs中,心肌炎可能导致患者死亡,需要临床予以重视。     

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...     

Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review

Introduction: Immune-related ocular toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of ocular toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors.

Areas covered: PubMed database has been searched till June 2016. Prospective clinical trials reporting the occurrence of immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eleven trials with 4965 participants were included. These studies included one study for ipilimumab and tremelimumab, three studies for nivolumab, five studies for pembrolizumab and one study comparing pembrolizumab to ipilimumab. No atezolizumab studies were included. The most common ocular toxicities reported with these agents included uveitis and dry eyes. Pooled analysis for odds ratio of all-grade immune-related ocular toxicities is 3.40 [95% CI: 1.32–8.71; P = 0.01].

Expert commentary: Despite being uncommon, immune-related ocular toxicities (particularly uveitis and dry eyes) occur with a higher frequency in cancer patients treated immune checkpoint inhibitors compared to those treated with control regimens.     

Tissue-resident memory T cells in immunotherapy and immune-related adverse events by immune checkpoint inhibitor

Tissue-resident memory T cells (TRM) are a specialized subset of T cells that reside in tissues and provide long-term protective immunity against pathogens that enter the body through that specific tissue. TRM cells have specific phenotype and reside preferentially in barrier tissues. Recent studies have revealed that TRM cells are the main target of immune checkpoint inhibitor immunotherapy since their role in cancer immunosurveillance. Furthermore, TRM cells also play a crucial part in pathogenesis of immune-related adverse events (irAEs). Here, we provide a concise review of biological characteristics of TRM cells, and the major advances and recent findings regarding their involvement in immune checkpoint inhibitor immunotherapy and the corresponding irAEs.     

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events

Objective:We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events (irAEs) as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors (ICIs) in patients with advanced pan-cancer in a real-world setting.Methods:We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1, 2016 and August 1, 2020. We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics, blood count parameters, and biochemical indicators during treatment. Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values. Kaplan–Meier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS).Results:A lower relative lymphocyte count (cutoff = 28.5%), higher albumin level (cutoff = 39.05 g/L), and higher absolute eosinophil count (AEC) (cutoff = 0.175 × 10⁹/L) were significantly associated with the occurrence of irAEs, among which a higher AEC (cutoff = 0.205 × 10⁹/L) was strongly associated with skin-related irAEs [odds ratios (ORs) = 0.163, P = 0.004]. Moreover, a higher lactate dehydrogenase level (cutoff = 237.5 U/L) was an independent predictor of irAEs of grade ≥ 3 (OR = 0.083, P = 0.023). In immune cell subgroup analysis, a lower absolute count of CD8⁺CD28⁻ suppressor T cells (OR = 0.806; 95% confidence interval: 0.643–1.011; P = 0.062), which are regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant. Furthermore, a higher percentage of CD19⁺ B cells was associated with the occurrence of irAEs of grade ≥ 3 (P = 0.02) and grade ≥ 2 (P = 0.051). In addition, patients with any grade of irAE had a significantly high PFS (8.37 vs. 3.77 months, hazard ratios (HR) = 2.02, P = 0.0038) and OS (24.77 vs. 13.83 months, HR = 1.84; P = 0.024).Conclusions:This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.     

PD-1单抗治疗非小细胞肺癌相关不良反应及其与疗效的相关性分析

背景与目的:随着免疫检查点抑制剂在肺癌中的应用增多,免疫相关不良反应(immune-related adverse event,irAE)受到越来越多的重视.分析使用单药免疫治疗肺癌患者的irAE发生情况及其与免疫治疗效果的相关性.方法:回顾性收集同济大学附属上海市肺科医院2015年6月—2019年1月接受抗程序性死亡...     

环氧合酶-2和表皮生长因子受体在非小细胞肺癌的表达及意义

目的 :探讨环氧合酶 2 (COX 2 )和表皮生长因子受体 (EGFR)在非小细胞肺癌 (NSCLC)中的表达与意义。方法 :应用免疫组织化学染色EnVision法检测 6 0例根治术后NSCLC肿瘤组织中COX 2和EGFR的表达。应用 χ2 检验和COX回归分析等比较COX 2和EGFR在不同分化级别的肺鳞癌和腺癌中表达上的差异及其与术后患者生存期之间的关系。结果 :77%肺腺癌表达COX 2 ,表达率明显高于肺鳞癌的 37% (χ2 =9.774 ,P <0 .0 1) ;NSCLC中COX 2和EGFR的表达与患者年龄、性别、肿瘤分化级别、原发灶大小、淋巴结转移范围和 p TNM分期等因素无关。COX 2表达“ ”和“ ”和EGFR表达“ ”与“ ”患者的中位生存期分别为 30个月和 16个月与 34个月和 15个月 ,均明显低于各自不表达患者的 4 5个月 (P <0 .0 5 )。COX多因素回归分析示COX 2表达和p TNM分期是影响该组NSCLC患者预后的两个独立因素。在肺鳞癌 ,EGFR也与预后不良有关。 结论 :COX 2和EGFR在NSCLC有表达 ,表达者预后较差。     

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。     

Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management

Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice.     

卡瑞利珠单抗治疗复发或晚期转移性食管鳞癌临床疗效及免疫相关不良反应观察

目的:探讨卡瑞利珠单抗治疗复发或晚期转移性食管鳞癌的临床疗效以及免疫相关不良反应。方法:回顾性分析88例复发或晚期转移性食管鳞癌患者的治疗经过和疗效,将患者随机分为免疫联合化疗组、化疗组各44例,统计客观缓解率（objective remission rate,ORR)、疾病控制率(disease control rate,DCR)、无进展生存期(progress free survival,PFS)、总生存期（overall survival,OS）,用Kaplan-Meier法绘制生存曲线,用log-rank检验进行影响PFS和OS的单因素分析、COX风险回归模型进行多因素分析,并观察免疫相关不良反应。结果:免疫联合化疗组和化疗组的ORR分别为8例（18%）和4例（9%）,DCR分别为31例（70%）和20例（45%）,免疫联合化疗较单纯化疗可延长患者mPFS（5.5个月vs 3.5个月,P=0.007）和mOS（11.25个月vs 7.75个月,P＜0.001）。ECOG评分、肿瘤分化程度和转移部位数量是PFS和OS的影响因素。免疫相关不良反应主要有毛细血管增生症、甲状腺功能减低、乏力、食欲减退等,但多为1-2级,经对症处理后均可缓解。结论:卡瑞利珠单抗联合化疗较单纯化疗在复发或晚期转移性食管鳞癌中可明显延长PFS和OS,临床疗效显著,且安全性良好。     

非小细胞肺癌预后影响因素分析

目的:探讨非小细胞肺癌(NSCLC)患者的预后相关因素。方法:对2005年6月-2006年6月我院收治的162例非小细胞肺癌患者的临床、病理资料进行回顾性研究,采用Kaplan-Meier和COX回归方法分析评价各因素对预后的影响。结果:单因素分析表明KPS评分、手术与否、临床分期、治疗状况及治疗前血小板(PLT)、癌胚抗原(CEA)和神经元特异性烯醇化酶(NSE)的水平与NSCLC患者的预后有关。多因素分析表明,临床分期、治疗状况、血小板及血清癌胚抗原的水平是独立的预后影响因素。临床分期Ⅳ期、未治疗、PLT>300×109/L、CEA>5.0μg/L时,相对危险度(RR)分别为5.524、16.096、3.563、2.607。结论:治疗前血小板、血清CEA的水平、临床分期及治疗情况是NSCLC患者独立的预后影响因素。     

晚期非小细胞肺癌患者免疫治疗的皮肤毒性反应:荟萃分析和系统评价

目的:采用循证医学的方法评价免疫治疗相关的皮肤毒性反应的发生风险。方法:电子检索PubMed、Web of Science、Embase和Cochrane library,纳入非小细胞肺癌免疫治疗的随机对照临床试验文献,检索时间为建库至2020年10月31日,采用STATA 12.0软件对数据进行Meta 分析。结果:共纳入14项研究,共7 906例患者。结果显示,免疫治疗的总体发生率、低级别皮肤不良反应、帕博利珠单抗出现皮肤毒性反应均高于化疗/安慰剂组,差异具有统计学意义(P＜0.05)。结论:免疫治疗出现低级别不良反应或者使用帕博利珠单抗时出现任何级别皮肤不良反应均高于化疗/安慰剂。     

Lung cancer survival in England: trends in non-small-cell lung cancer survival over the duration of the National Lung Cancer Audit

Background:

In comparison with other European and North American countries, England has poor survival figures for lung cancer. Our aim was to evaluate the changes in survival since the introduction of the National Lung Cancer Audit (NLCA).

Methods:

We used data from the NLCA to identify people with non-small-cell lung cancer (NSCLC) and stratified people according to their performance status (PS) and clinical stage. Using Cox regression, we calculated hazard ratios (HRs) for death according to the year of diagnosis from 2004/2005 to 2010; adjusted for patient features including age, sex and co-morbidity. We also assessed whether any changes in survival were explained by the changes in surgical resection rates or histological subtype.

Results:

In this cohort of 120 745 patients, the overall median survival did not change; but there was a 1% annual improvement in survival over the study period (adjusted HR 0.99, 95% confidence interval (CI) 0.98–0.99). Survival improvement was only seen in patients with good PS and early stage (adjusted HR 0.97, 95% CI 0.95–0.99) and this was partly accounted for by changes in resection rates.

Conclusion:

Survival has only improved for a limited group of people with NSCLC and increasing surgical resection rates appeared to explain some of this improvement.     

Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature

Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related disorders. We here review the literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3.8% with anti-CTLA4 antibodies, 6.1% with anti-PD1 antibodies, and 12.0% with the combination of both. The clinical spectrum of neurological disorders was highly heterogeneous. Most of these nAEs were grade 1–2 and consisted of non-specific symptoms such as headache (55%). The incidence of high grade nAEs was below 1% for all types of treatment. Headaches, encephalopathies and meningitis were the most commonly reported (21%, 19% and 15%, respectively). Among the 27 case reports, the most common nAEs were encephalopathies, meningoradiculoneuritis, Guillain-Barré like syndromes and myasthenic syndromes. The median time of nAEs onset was 6 weeks. In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-Barré syndrome.