Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types.
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ABSTRACT:
SUBMITTER: Wang F
PROVIDER: S-EPMC8433190 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
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Real-world data analyses unveiled the immune-related adverse effects of immune checkpoint inhibitors across cancer types.
Wang Feicheng F Yang Shihao S Palmer Nathan N Fox Kathe K Kohane Isaac S IS Liao Katherine P KP Yu Kun-Hsing KH Kou S C SC
NPJ precision oncology 20210910 1
Immune checkpoint inhibitors have demonstrated significant survival benefits in treating many types of cancers. However, their immune-related adverse events (irAEs) have not been systematically evaluated across cancer types in large-scale real-world populations. To address this gap, we conducted real-world data analyses using nationwide insurance claims data with 85.97 million enrollees across 8 years. We identified a significantly increased risk of developing irAEs among patients receiving immu ...[more]
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Project description:BackgroundImmune checkpoint inhibitors (ICIs) can cause life-threatening cardiovascular adverse events (CVAEs) that may not be attributed to therapy. The outcomes of clinical trials may underestimate treatment-related adverse events due to restrictive eligibility, limited sample size, and failure to anticipate selected toxicities. We evaluated the incidence and clinical determinants of CVAEs in real-world population on ICI therapy.Patients and methodsAmong 2 687 301 patients diagnosed with cancer from 2011 to 2018, 16 574 received ICIs for any cancer. Patients in the ICI and non-ICI cohorts were matched in a 1 : 1 ratio according to age, sex, National Cancer Institute comorbidity score, and primary cancer. The non-ICI cohort was stratified into patients who received chemotherapy (N = 2875) or targeted agents (N = 4611). All CVAEs, non-cardiac immune-related adverse events occurring after treatment initiation, baseline comorbidities, and treatment details were identified and analyzed using diagnosis and billing codes.ResultsMedian age was 61 and 65 years in the ICI and non-ICI cohorts, respectively (P < 0.001). ICI patients were predominantly male (P < 0.001). Lung cancer (43.1%), melanoma (30.4%), and renal cell carcinoma (9.9%) were the most common cancer types. CVAE diagnoses in our dataset by incidence proportion (ICI cohort) were stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). Anti-cytotoxic T-lymphocyte-associated protein 4 increased the risk of heart failure [versus anti-programmed cell death protein 1; hazard ratio (HR), 1.9; 95% confidence interval (CI) 1.27-2.84] and stroke (HR, 1.7; 95% CI 1.3-2.22). Pneumonitis was associated with heart failure (HR, 2.61; 95% CI 1.23-5.52) and encephalitis with conduction disorders (HR, 4.35; 95% CI 1.6-11.87) in patients on ICIs. Advanced age, primary cancer, nephritis, and anti-cytotoxic T-lymphocyte-associated protein 4 therapy were commonly associated with CVAEs in the adjusted Cox proportional hazards model.ConclusionsOur findings underscore the importance of risk stratification and cardiovascular monitoring for patients on ICI therapy.
| S-EPMC8403739 | biostudies-literature
Project description:IntroductionImmunotherapy represents a key pillar of cancer treatments, with high response rates and long survival. Its use is increasing, mainly at the expense of the geriatric population due to the ageing of this population. However, despite its benefit, its safety in certain areas such as cardiotoxicity is largely unknown. The aim of this study is to assess the safety of immunotherapy in elderly patients using real-world data.MethodsThis is an ambispective study of patients ≥ 70 years old with solid tumours who were treated with immunotherapy at the University Hospital of Salamanca. Cardiotoxicity was assessed using the CTCAEv5.0 criteria.ResultsIn total, 195 patients were included (76.9% male and 23.1% female), with a mean age of 75 years [70-93]. The percentage of patients with cardiotoxicity was 1.54%; 1.35% of patients with previous heart disease were diagnosed with cardiotoxicity, and 1.65% of those without previous heart disease were diagnosed with cardiotoxicity. The median time from the initiation of treatment until the cardiac event was 45 days [14-96]. The most frequent toxicity was myocarditis in 66.7% of patients, followed by arrhythmias in 33.3% of patients.ConclusionsImmunotherapy is shown to be a safe treatment in elderly cancer patients in terms of cardiotoxicity. The event rate shows no difference between patients with or without cardiac comorbidity.
| S-EPMC10486692 | biostudies-literature
Project description:BackgroundReal-world evidence on immune-related adverse events (irAEs) are relatively insufficient. Herein patterns and outcomes of irAEs after administration of anti-programmed cell death 1 (PD-1) and its legend 1 (PD-L1) antibodies were investigated.MethodsPatients treated with anti-PD-1/PD-L1 drugs from January 2018 to September 2021 at Huadong Hospital, Fudan University were included. Common Terminology Criteria for Adverse Events (CTCAE) was used for irAEs evaluation. The primary endpoints were the clinical description of irAEs.ResultsTwo hundred and forty-one solid tumor patients were included, with lung cancer as the most common tumor type (56%). 187 (77.6%) patients presented any kind of irAEs. The median time to any irAE onset was 28 (95% CI 24-32) days. Skin toxicities are the most common irAEs (46.1%) and the irAEs (36.5%) occurred earliest after immune-checkpoint inhibitors. The most frequently occurred all-grade irAEs were rash (23.7%), myelosuppression (20.7%), and hepatic injury (19.5%). 23 (9.5%) patients died of severe irAEs, which consists of 10 patients with pneumonitis, four colitis, four myocarditis, and one each for gastritis, pulmonary embolism, myelosuppression, hypophysitis, and encephalitis. Patients with any irAE onset had significantly longer progression-free survival (PFS) (p = 0.013) and overall survival (OS) (p = 0.007), respectively, than patients without irAEs. In addition, patients with skin toxicities (p = 0.012) or blood toxicities (p = 0.015) had achieved a longer PFS, than those without corresponding toxitities, respectively.ConclusionMost irAEs are mild and manageable, while some irAEs can present at later time or can be life-threatening, especially pneumonitis as we observed. Patients with any irAE onset may achieve a better prognosis than those without irAEs, and presentation of skin or blood toxicities will indicate a better PFS.
| S-EPMC10557884 | biostudies-literature
Project description:BackgroundWith increased use of immune checkpoint inhibitors (ICIs) among patients with cancer, there is substantial interest in understanding clinical and economic outcomes and management of immune-related adverse events (irAEs).Patients, materials, and methodsA retrospective study was conducted using Premier Healthcare Database, a U.S. national hospital discharge database, from March 1, 2015, through December 31, 2017. The database comprises more than 880 million inpatient and hospital-based outpatient encounters, with more than 200 million unique patients reported by 966 hospitals. Patients with four solid tumors known to benefit from ICI therapy were included. The list of irAEs assessed was defined a priori per American Society of Clinical Oncology clinical guidelines for irAE management. Baseline irAE-related inpatient and outpatient visits were defined as the first inpatient or hospital-based outpatient visit with discharge diagnosis of any irAE of interest following confirmed ICI usage within 90 days prior to the baseline visit. Patients were followed for 90 days after baseline irAE-related inpatient discharge date or outpatient visit date to assess irAE-related inpatient admissions, all-cause in-hospital mortality, ICI reinitiation, and to determine costs and health care resource utilization.ResultsRecords from 673,957 patients with four tumor types were reviewed for ICI therapy. Of 13,030 patients receiving ICIs, approximately 40% experienced at least one irAE, with a total of 10,121 irAEs occurring within 90 days of the ICI visit. The most frequent (>1,000 events) irAEs were anemia, impaired ventricular function with heart failure and vasculitis, thrombocytopenia, thyroid conditions, and peripheral edema. As might be expected, compared with those with baseline irAE-related outpatient visits, patients with baseline irAE-related inpatient visits had a significantly higher percentage of irAE-related inpatient admissions (23% vs. 14%) and all-cause in-hospital mortality (22% vs. 6%) and lower reinitiation of ICI therapy (31% vs. 71%). Baseline irAE-related inpatient visits had significantly higher mean costs ($29,477 vs. $5,718) with longer hospital stays (12.6 vs. 7.8 days).ConclusionFindings from a U.S. national hospital discharge database suggest that irAEs in patients treated with ICIs are common, occur in multiples and with greater frequency in those with pre-existing comorbidities. Those with inpatient admissions have poorer outcomes.Implications for practiceThe present work addressed the knowledge gap in understanding real-world outcomes of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). Patients who experienced irAEs had significantly higher baseline comorbidities and were more likely to have immune-related or immune-compromised comorbid conditions. Patients with baseline irAE-related hospitalizations were more likely to be rehospitalized and to experience in-hospital mortality and less likely to reinitiate ICI treatment. Real-world patients are more diverse than clinical trials, and clinicians should consider both the efficacy and safety profile of ICI treatments, especially for patients with comorbidity conditions. Close monitoring is needed after patients have experienced an irAE.
| S-EPMC8571769 | biostudies-literature
Project description:BackgroundPatients treated with immunotherapy in the real-world may have significantly different responses to those meeting inclusion criteria for random controlled clinical studies. There is a partial overlap in approved indications for the use of the different immune checkpoint inhibitors (ICIs) currently available. A comprehensive assessment of the efficacy, safety and economic effects of various ICIs is a problem that clinicians need to address.MethodsAnalyzed real-world data was collected from non-small cell lung cancer (NSCLC) patients who were treated with ICIs from hospitalized patients in the Lung Cancer Center of Peking Union Medical College Hospital between 2018 and 2021. The objectives were to evaluate the efficacy and safety of different ICIs for the treatment of NSCLC in China and to investigate the factors affecting their curative effects.ResultsOverall, 351 patients were included in the retrospective study. The median PFS for the NSCLC patient cohort treated with medication regimens that included ICIs was 9.5 months, with an ORR of 47.3%. There were no significant discrepancies in efficacy and safety between the different ICIs administered. Factors that had the greatest impact on the efficacy of ICIs were the disease stage, ECOG-PS scores and treatment lines. Gender, age, smoking history, PD-L1 TPS expression, history of targeted therapy and irAEs all had a degree of influence on patient prognosis.ConclusionsThe study reports the experience of real-world usage of ICIs for the treatment of NSCLC patients in China. The results were generally consistent with those of clinical trials, while the efficacy and safety of different ICIs exhibited no statistically significant differences. Therefore, physicians can make a comprehensive choice based on the indications and cost of different ICIs and the preferences of patients.
| S-EPMC8982065 | biostudies-literature
Project description:Uveal melanoma (UM) is the most common intraocular malignancy in adults and shows a high rate of metastatic spread. As randomized clinical trials with immune checkpoint inhibitors (ICI) have not been performed in patients with metastatic UM, we analyzed the real-world outcomes in a nationwide population-based study. Clinical data of patients with UM were extracted from the Danish Metastatic Melanoma database, a nationwide database containing unselected records of patients diagnosed with metastatic melanoma in Denmark. Survival before (pre-ICI, n = 32) and after (post-ICI, n = 94) the approval of first-line treatment with ICI was analyzed. A partial response to first-line treatment was observed in 7% of patients treated with anti-programmed cell death protein (PD)-1 monotherapy and in 21% with combined anti-cytotoxic T lymphocyte antigen (CTLA)-4 plus anti-PD-1 therapy. Median progression-free survival was 2.5 months for patients treated in the pre-ICI era compared to 3.5 months in the post-ICI era (hazard ratio (HR) 0.43; 95% confidence interval (CI) 0.28-0.67; p < 0.001). The estimated one-year overall survival rate increased from 25.0% to 41.9% and the median overall survival improved from 7.8 months to 10.0 months, respectively (HR 0.52; 95% CI 0.34-0.79; p = 0.003). Thus, the introduction of ICI as first-line treatment appears to have significantly improved the real-world survival of patients with metastatic UM, despite relatively low response rates compared to cutaneous melanoma. With the lack of therapies proven effective in randomized trials, these data support the current treatment with ICI in patients with metastatic UM.
| S-EPMC6826482 | biostudies-literature
Project description:BACKGROUND:Immune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs. METHODS:This study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant. RESULTS:A total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93-1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025 = 2.49 and ROR025 = 5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR = 1.68 (95%CI 1.55-1.83), ROR = 2.54 (95%CI 2.20-2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR = 2.00, 95%CI 1.89-2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N = 885,14.14%), adrenal insufficiency(N = 730,11.66%), hypophysitis (N = 688,10.99%) and hyperthyroidism (N = 472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies. CONCLUSION:Our pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.
| S-EPMC6836403 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICIs), the treatment of multiple cancer types, can be associated with respiratory system adverse events (AEs). The aim of this study is to quantify the association of respiratory system AEs and ICIs and to characterize the profiles of ICI-related respiratory system complications from Food and Drug Administration Adverse Event Reporting System (FAERS) data.MethodsThe disproportionality of respiratory system AE-related ICIs based on FAERS data from January 2014 to September 2021 was analyzed using the reporting odds ratio (ROR) and information component (IC) as measures of potential risk increase.ResultsA total of 38,415,849 records were involved; among these, 36,923 records related to respiratory system AEs after ICI treatment were identified. In the first 3 months, the cumulative proportion of respiratory system AEs was 75.40%. Men had a slightly higher reporting frequency than that of women (ROR = 1.74, 95% CI: 1.70-1.78). Death cases had a slightly higher reporting frequency in ICI-associated respiratory system AEs than that of other drug-associated respiratory system AEs (ROR = 1.40, 95% CI: 1.38-1.41). Anti-programmed cell death 1 (PD-1) drugs and anti-programmed cell death ligand 1 (PD-L1) drugs were significantly associated with respiratory system toxicities. However, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drugs did not demonstrate an association with respiratory system toxicities. Interstitial lung disease and pneumonitis were found to be significantly associated with all eight types of ICIs. In addition, 7 in 10 class-specific respiratory system AEs (lower respiratory tract disorders, pleural disorders, pulmonary vascular disorders, respiratory disorders not elsewhere classified (NEC), respiratory tract infections, respiratory tract neoplasms, and thoracic disorders) were associated with ICIs. The signal values of IC025 were from 0.08 to 2.66.ConclusionsOverall, this study showed a high reporting frequency of respiratory system toxicities caused by ICIs. Early recognition and management of ICI-related respiratory system AEs are of vital importance in practice. Maximizing the benefit while reducing potential respiratory system toxicities of ICIs should become a priority.
| S-EPMC9437516 | biostudies-literature
Project description:The advent of immune checkpoint inhibitors (ICIs) caused a paradigm shift both in drug development and clinical practice; however, by virtue of their mechanism of action, the excessively activated immune system results in a multitude of off-target toxicities, the so-called immune-related adverse events (irAEs), requiring new skills for timely diagnosis and a multidisciplinary approach to successfully manage the patients. In the recent past, a plethora of large-scale pharmacovigilance analyses have characterized various irAEs in terms of spectrum and clinical features in the real world. This review aims to summarize and critically appraise the current landscape of pharmacovigilance studies, thus deriving take-home messages for oncologists. A brief primer to study design, conduction, and data interpretation is also offered. As of February 2020, 30 real-world postmarketing studies have characterized multiple irAEs through international spontaneous reporting systems, namely WHO Vigibase and the US FDA Adverse Event Reporting System. The majority of studies investigated a single irAE and provided new epidemiological evidence about class-specific patterns of irAEs (i.e. anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] versus anti-programmed cell death 1 [PD-1] receptor, and its ligand [PD-L1]), kinetics of appearance, co-occurrences (overlap) among irAEs, and fatality rate. Oncologists should be aware of both strengths and limitations of these pharmacovigilance analyses, especially in terms of data interpretation. Optimal management (including rechallenge), predictivity of irAEs (as potential biomarkers of effectiveness), and comparative safety of ICIs (also in terms of combination regimens) represent key research priorities for next-generation real-world studies.
| S-EPMC7434791 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have been approved for monotherapy and combined therapy with chemotherapy and/or radiotherapy in China since 2018. The number of patients receiving ICIs has significantly increased in recent years, and the collection and analysis of this data are crucial for a comprehensive understanding of their clinical outcomes and adverse effects. The effects of ICIs may vary among different ethnic groups, and there is a lack of such data in the Chinese population. This study aimed to investigate the occurrence rate of various types of immune-related adverse events (irAEs) of ICIs in cancer survivors with different types of cancer and explore the associated risk factors. Demographic data, cancer type, dosage, Eastern Cooperative Oncology Group Performance Score (ECOG-PS), and details of irAEs were collected from 120 participants who underwent ICI treatment. Descriptive statistics were used to summarise the patient population characteristics, while t-tests and Chi-square tests assessed associations between variables. Multiple logistic regression evaluated the relationships between independent variables and the likelihood of experiencing irAEs. The results indicated that the occurrence of less severe G1 and G2 irAEs was 25%, while more severe G3 to G5 irAEs accounted for 5.8% of the total. Among the irAEs, skin toxicity had the highest incidence rate (14.2%), followed by gastrointestinal toxicity (6.7%), and endocrine toxicity had the lowest incidence rate of 2.5%. The multiple logistic regression model revealed that patients with ECOG-PS ≥ 2 are over five times more likely to experience irAEs compared to those with lower ECOG-PS (OR: 5.03, 95% CI: 1.05-24.17). Additionally, patients with cancer stage IV have 11.47 times the odds of experiencing irAEs (OR: 11.47, 95% CI: 1.05-24.17). In conclusion, a substantial proportion of patients receiving ICIs experienced irAEs. Patients with an ECOG-PS score of ≥ 2 and advanced cancer stage are at increased risk for these events, necessitating close monitoring by healthcare professionals. The identification of skin and gastrointestinal toxicities as the most common irAEs revealed the need for targeted education for the patients and their carers to recognise and manage these issues. Furthermore, our findings, in conjunction with existing literature, may guide future research on predictive modelling for high-risk patients receiving ICIs.
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