Association between Early Immune-Related Adverse Events and Survival in Patients Treated with PD-1/PD-L1 Inhibitors.
Ontology highlight
ABSTRACT: Background
Immune-related adverse events (irAEs) are side effects that reflect the activation of patients' immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between early irAEs and the survival of patients treated with ICIs.Methods
PubMed, Embase, and Web of Science were searched from May 2010 to May 2020 for all the retrospective and prospective comparative studies to evaluate the hazard ratios (HRs) for death. A random-effects model was used to calculate the pooled HR for death, and heterogeneity was assessed using I² statistics. The main outcomes were overall survival (OS) and progression-free survival (PFS).Results
A total of 11 reports with 2077 patients were included. A significant association was observed between early irAEs and a favorable clinical outcome. Patients with early irAEs had prolonged OS (HR: 0.62, 95% confidence interval (CI): 0.53-0.74, p < 0.001) and PFS (HR: 0.53, 95% CI: 0.41-0.66, p < 0.001) compared to those without; these results were confirmed using a sensitivity analysis. The irAE types, malignancy types, and sample size were correlated with patients' clinical outcomes.Conclusions
Early irAEs, especially cutaneous irAEs, correlated with a better clinical outcome in patients treated with ICIs.
SUBMITTER: Zhang YC
PROVIDER: S-EPMC9917734 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Publications
Association between Early Immune-Related Adverse Events and Survival in Patients Treated with PD-1/PD-L1 Inhibitors.
Zhang You-Cheng YC Zhu Tian-Chen TC Nie Run-Cong RC Lu Liang-He LH Xiang Zhi-Cheng ZC Xie Dan D Luo Rong-Zhen RZ Cai Mu-Yan MY
Journal of clinical medicine 20230117 3
<h4>Background</h4>Immune-related adverse events (irAEs) are side effects that reflect the activation of patients' immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between early irAEs and the survival of patients treated with ICIs.<h4>Methods</h4>PubMed, Embase, and Web of Science were searched from May 2010 to May 2020 for all the retrospective and prosp ...[more]
Similar Datasets
Project description:BackgroundThyroid immune-related adverse events (IRAEs) have been reported in patients treated with programmed cell death protein-1 (PD-1) and programmed cell death protein-ligand 1 (PD-L1) inhibitors. We investigated the incidence and clinical course of PD-1/PD-L1 inhibitor-induced thyroid IRAEs, and identified predictable clinical risk factors of thyroid IRAEs, in particular, overt hypothyroidism (OH).MethodsWe retrospectively reviewed the medical records of 325 cancer patients receiving PD-1/PD-L1 inhibitor in a tertiary referral center.ResultsA total of 50.5% (164/325) of patients experienced at least one abnormal thyroid function following PD-1/PD-L1 inhibitor. Eighty-four patients (51.2%) of them recovered to normal thyroid function during follow-up. In overall population, 25 patients (7.7%) required thyroid hormone replacement therapy due to PD-1/PD-L1 inhibitor-induced OH. Patients who progressed to OH showed significantly higher baseline thyroid stimulating hormone level and longer duration of PD-1/PD-L1 inhibitor therapy than those without thyroid dysfunction or OH (both P<0.001). Median time interval to the development of OH was 3 months after the therapy. OH was significantly associated with positive anti-thyroid peroxidase antibody at baseline and anti-thyroglobulin antibody during the therapy than those without thyroid dysfunction or OH (P=0.015 and P=0.005, respectively). We observed no patients with OH who were able to stop levothyroxine replacement after the cessation of PD-1/PD-L1 inhibitor therapy.ConclusionPD-1/PD-L1 inhibitor-induced thyroid dysfunctions are considerably reversible; however, OH is irreversible requiring levothyroxine replacement even after stopping the therapy. Positive thyroid autoantibodies may predict the progression to OH.
| S-EPMC8090457 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far.MethodsThe prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE.ResultsBetween April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were "weight change", "difficulty to grip things", "bloody or mucous stool" and "insomnia". Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire.ConclusionQuestionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on "weight change" and "insomnia" may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients.Trial registrationClinicalTrials.gov, NCT03453892 . Registered on 05 March 2018.
| S-EPMC7992796 | biostudies-literature
Project description:BackgroundMetabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related adverse events (irAEs) occurrence. However, there is a lack of reliable metabolic biomarkers to predict irAEs. This study aims to explore the potential metabolic biomarkers to predict risk of irAEs and to investigate the association of plasma metabolites level with survival in patients with lung cancer receiving PD-1/PD-L1 inhibitor treatment.MethodsThe study collected 170 plasmas of 85 patients with lung cancer who received immune checkpoint inhibitors (ICIs) treatment. 58 plasma samples of 29 patients with irAEs were collected before ICIs treatment and at the onset of irAEs. 112 plasma samples of 56 patients who did not develop irAEs were collected before ICIs treatment and plasma matched by treatment cycles to onset of irAEs patients. Untargeted metabolomics analysis was used to identify the differential metabolites before initiating ICIs treatment and during the process that development of irAEs. Kaplan-Meier curves analysis was used to detect the associations of plasma metabolites level with survival of patients with lung cancer.ResultsA total of 24 differential metabolites were identified to predict the occurrence of irAEs. Baseline acylcarnitines and steroids levels are significantly higher in patients with irAEs, and the model of eight acylcarnitine and six steroid metabolites baseline level predicts irAEs occurrence with area under the curve of 0.91. Patients with lower concentration of baseline decenoylcarnitine(AcCa(10:1) 2, decenoylcarnitine(AcCa(10:1) 3 and hexanoylcarnitine(AcCa(6:0) in plasma would have better overall survival (OS). Moreover, 52 differential metabolites were identified related to irAEs during ICIs treatment, dehydroepiandrosterone sulfate, corticoserone, cortisol, thyroxine and sphinganine 1-phaosphate were significantly decreased in irAEs group while oxoglutaric acid and taurocholic acid were significantly increased in irAEs group.ConclusionsHigh levels of acylcarnitines and steroid hormone metabolites might be risk factor to development of irAEs, and levels of decenoylcarnitine (AcCa(10:1) 2, decenoylcarnitine (AcCa(10:1) 3 and hexanoylcarnitine (AcCa(6:0) could be used to predict OS for patients with lung cancer received ICIs treatment.
| S-EPMC11243122 | biostudies-literature
Project description:Immune-related cutaneous adverse events (irCAEs) in patients treated with programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors may be associated with better clinical outcomes. However, the extent to which these results can be extrapolated to all tumour types remains unclear. Herein, we conducted a meta-analysis of patients with cancer receiving anti-PD-1/PD-L1 immunotherapy, to determine the cumulative incidence of irCAEs and their association with survival. We systematically searched six databases (PubMed, Embase, Cochrane, CNKI, CSPD, and CQVIP database) for all cohort studies reporting the relationship between irCAEs and patient survival from the time of database construction to 1 November, 2020. The primary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), with complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) as secondary outcomes. Patients with irCAEs exhibited higher ORR, and were more likely to report CR and PR and less likely to develop PD than those who did not experience irCAEs. Moreover, the occurrence of irCAEs was significantly associated with both favourable PFS and OS. Therefore, patients with irCAEs have better survival benefit and a significantly lower risk of tumour progression or death. Hence, the occurrence of irCAEs may be a useful marker for predicting the clinical efficacy of anti-PD-1/PD-L1 immunotherapy.
| S-EPMC9681870 | biostudies-literature
Project description:While some literature has provided limited information about the potential cardiovascular risk and immune-related adverse events (irAEs) risk associated with PD-1/PD-L1 inhibitors in the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC), the exact relevance is still uncertain. To assess the pharmacovigilance (PV), constituent ratio, severity, and reaction outcomes of major adverse cardiovascular events (MACE) and immune-related adverse events (irAEs) related to PD-1/PD-L1 inhibitors for HNSCC reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed reports of cardiovascular adverse events and irAEs associated with drug therapy for HNSCC submitted to FAERS from the 1st quarter 2015 to the 3rd quarter of 2023. Three PD-1/PD-L1 inhibitors were identified: nivolumab, pembrolizumab and durvalumab. Our primary composite endpoint was the PV of MACE and irAEs related to PD-1/PD-L1 inhibitors in the treatment of HNSCC, and the secondary endpoint was PV of other cardiovascular events. The software implemented was STATA 17.0 MP. 19,372 suspected drug-adverse event reports related to drug treatment in patients with HNSCC were identified, of which 916 reports were cardiovascular events, including 555 reports of MACE and 361 reports of other cardiovascular events. The PV signal regarding MACE was detected in durvalumab (PRR = 2.12, 95% CI: 1.24-3.61; χ2 = 7.71; ROR = 2.19, 95% CI: 1.24-3.86; IC = 1.01; IC025 = 0.07) but not in nivolumab and pembrolizumab. The constituent ratio of MACE in all adverse events caused by nivolumab (OR = 0.38, 95% CI: 0.19-0.73) and pembrolizumab (OR = 0.48, 95% CI: 0.23-0.99) was significantly decreased, compared with durvalumab. A PV signal about other cardiovascular events was detected in durvalumab (PRR = 3.04, 95% CI: 1.73-5.31; χ2 = 16.13; ROR = 3.15, 95% CI: 1.74-5.70; IC = 1.46; IC025 = 0.48), but it was not detected in nivolumab or pembrolizumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR = 0.25, 95% CI: 0.13-0.48) and pembrolizumab (OR = 0.40, 95% CI: 0.20-0.80) was significantly decreased, compared with durvalumab. The constituent ratio of other cardiovascular events in all adverse events caused by nivolumab (OR = 0.61, 95% CI: 0.38-0.99) was significantly decreased, compared with pembrolizumab. There were 40 cases of hypertension. A PV signal about hypertension was detected in pembrolizumab (PRR = 3.72, 95% CI: 1.87-7.43; χ2 = 15.99; ROR = 3.75, 95% CI: 1.87-7.51; IC = 1.53, IC025 = 0.45), but it was not detected in nivolumab. The constituent ratio of hypertension in all adverse events caused by nivolumab (OR = 0.09, 95% CI: 0.09-0.39) was significantly decreased, compared with pembrolizumab. There were 737 cases of irAEs. A PV signal about irAEs was detected in nivolumab (PPR = 1.27, 95% CI: 1.05-1.53; χ2 = 6.38; ROR = 1.28, 95% CI: 1.06-1.56; IC = 0.29, IC025 = -0.00) and pembrolizumab (PPR = 2.20, 95% CI: 1.79-2.71; χ2 = 56.55; ROR = 2.31, 95% CI: 1.84-2.88; IC = 1.03; IC025 = 0.68), but it was not detected in durvalumab. The constituent ratio of irAEs in all adverse events caused by nivolumab (OR = 0.58, 95% CI: 0.44-0.76) significantly decreased, compared with pembrolizumab. By comparing the PV signals, constituent ratio, severity, and reaction outcome of the three drugs, we suppose that nivolumab can be used as the safest PD-1/PD-L1 inhibitor for HNSCC.
| S-EPMC11522629 | biostudies-literature
Project description:IntroductionImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapeutics. However, immune-related adverse events (irAEs) increase morbidity and mortality and thereby limit therapeutic utility. The real-world incidence of the entire spectrum of pulmonary irAEs has not been systematically described. The objective of this study is to assess the risk of developing pulmonary irAEs (pneumonitis, pleural events [i.e., effusion and pleurisy], exacerbations of airway disease [i.e., bronchitis and bronchiectasis], and sarcoidosis) with exposure to five commonly used ICIs: nivolumab, pembrolizumab, durvalumab, avelumab, and atezolizumab.MethodsWe conducted a retrospective review of the Food and Drug Administration Adverse Events Reporting System (FAERS) pharmacovigilance database. We collected data from 2012 to 2021 to assess the risk of pulmonary irAEs and performed a disproportionality analysis using Open-Vigil, a software package used for analysis of pharmacovigilance data, to calculate reporting odds ratios (RORs). We used 95% CIs to evaluate the precision of RORs. An ROR greater than 1 and the upper limit of the 95% CI indicated statistical significance.ResultsA total of 17,273,403 events were reported in FAERS between 2012 and 2021. Of these, 88,099 (0.5%) were attributed to the PD-1 (programmed cell death protein 1) inhibitors and 21,905 (0.1%) to PD-L1 (programmed death ligand 1) inhibitors of interest. The most common indication for using the ICIs of interest was lung cancer: a total of 2832 (46.70%) for the PD-1 inhibitors and 1311 (70.9%) for the PD-L1 inhibitors. In the anti-PD-1 group, 2342 (38.6%) patients were hospitalized, and 1962 (32.4%) patients died from the lung adverse event. In the PD-L1 group, 744 (40.3%) patients were hospitalized, and 520 (28.1%) patients died from the event. Nivolumab resulted in the highest statistically significant risk (ROR, 10.5; 95% CI, 10.1-10.9) for pneumonitis. Avelumab had a lesser risk for pneumonitis (ROR, 0.2; 95% CI, 0.2-0.3). The risk for pleural events was highest with nivolumab (ROR, 3.6; 95% CI, 3.4-3.9), followed by pembrolizumab (ROR, 1.8; 95% CI; 1.6-2.0) (p < 0.001), with the lowest risks from durvalumab, atezolizumab, and avelumab. For ICI-related sarcoidosis, the risk was most significant with pembrolizumab (ROR, 3.6; 95% CI, 2.8-4.7), followed by nivolumab (ROR, 2.5; 95% CI, 1.9-3.5) (p < 0.001). The RORs for all five ICIs were less than 1 for exacerbations of airway diseases as compared with other drugs.ConclusionUsing a pharmacovigilance database, we found an increased risk of multiple pulmonary irAEs after ICI therapy, particularly with PD-1 inhibitors. Further work is needed to investigate the incidence of pulmonary irAEs other than pneumonitis.
| S-EPMC10734392 | biostudies-literature
Project description:ImportanceImmune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined.ObjectiveTo examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs.Design, setting, and participantsThis retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line.ExposureDeveloping an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs).Main outcomes and measuresThe primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS.ResultsAmong the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001).Conclusions and relevanceIn this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.
| S-EPMC10797458 | biostudies-literature
Project description:Non-small-cell lung cancer takes up the majority of lung carcinoma-caused deaths. It is reported that targeting PD-1/PD-L1, a well-known immune evasion checkpoint, can eradicate tumor. Checkpoint inhibitors, such as monoclonal antibodies, are actively employed in cancer treatment. Thus, this review aimed to assess the therapeutic and toxic effects of PD-1/PD-L1 inhibitors in treatment of NSCLC. So far, 6 monoclonal antibodies blocking PD-1/PD-L1 interaction are identified and used in clinical trials and randomized controlled trials for NSCLC therapy. These antibody-based therapies for NSCLC were collected by using search engine PubMed, and articles about the assessment of adverse events were collected by using Google search. Route of administration and dosage are critical parameters for efficient immunotherapy. Although antibodies can improve overall survival and are expected to be target-specific, they can cause systemic adverse effects in the host. Targeting certain biomarkers can limit the toxicity of adverse effects of the antibody-mediated therapy. Clinical experts with knowledge of adverse effects (AEs) of checkpoint inhibitors can help manage and reduce mortalities associated with antibody-based therapy of NSCLC.
| S-EPMC8493325 | biostudies-literature
Project description:Immune-related adverse events (irAE) have been described with immune checkpoint inhibitors (ICI), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab, or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6,528 received an ICI (nivolumab, 1,534; pembrolizumab, 1,522; atezolizumab, 751; and ipilimumab, 2,721) and 4,926 had not. Compared with non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P < 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P < 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared with PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications. Cancer Immunol Res; 5(4); 312-8. ©2017 AACR.
| S-EPMC5418853 | biostudies-literature
Project description:BackgroundProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors are increasingly used in China, but no real-world data are available about the immune-related adverse events (irAEs). This real-world retrospective study aimed to assess the safety and effectiveness of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC) and to analyze the association between irAEs and effectiveness.MethodsThis was a retrospective study of the clinical data of patients with NSCLC treated with PD-1/PD-L1 inhibitors from August 2016 to November 2019 at Beijing Cancer Hospital. The patients were divided into the irAE or non-irAE groups. Overall adverse events, the impact of irAE on tumor response, and the association of irAEs with effectiveness were evaluated.ResultsOne hundred and ninety-one patients were included, including 70 (36.6%) patients in the irAE group and 121 (63.4%) patients in the non-irAE group. AE, grades 3-5 AEs, and irAE occurred in 107 (56.0%), 24 (12.6%), and 70 (36.6%) of the patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were higher in the irAE group compared with the non-irAE group (42.0% vs. 25.8%, P=0.038; 91.9% vs. 70.8%, P=0.002). Multivariable analyses identified that irAE were associated with progression-free survival (HR=0.62, 95%CI: 0.43-0.91; P=0.015), but not with overall survival (HR=0.76, 95%CI: 0.44-1.28; P=0.299).ConclusionIn NSCLC treated with PD-1/PD-L1 inhibitors, patients with irAEs showed improved effectiveness over patients without irAEs. Future studies of anti-PD-1/PD-L1 immunotherapy should explore this association and the underlying biological mechanisms of efficacy.
| S-EPMC7973369 | biostudies-literature