Dataset Information

Comparative Risk of Renal Adverse Events in Patients Receiving Immune Checkpoint Inhibitors: A Bayesian Network Meta-Analysis.

ABSTRACT:

Background

Immune checkpoint inhibitors (ICIs) have brought a paradigm shift to cancer treatment. However, little is known about the risk of renal adverse events (RAEs) of ICI-based regimens, especially ICI combination therapy.

Methods

We carried out a network meta-analysis of randomized controlled trials (RCTs) to compare the risk of RAEs between ICI-based regimens and traditional cancer therapy, including chemotherapy and targeted therapy. Subgroup analysis was conducted based on tumor types.

Results

Ninety-five eligible RCTs involving 40,552 participants were included. The overall incidence of RAEs, grade 3-5 RAEs, acute kidney injury (AKI), and grade 3-5 AKI was 4.3%, 1.2%, 1.3%, and 0.8%, respectively. Both ICI-based treatment regimens and traditional cancer therapy showed significantly higher risk of RAEs and AKI than the placebo. Among ICI monotherapy, anti-PD-1 (RR: 0.51, 95%CI: 0.29-0.91) was significantly safer than anti-CTLA-4 in terms of RAEs. Anti-CTLA-4 showed significantly higher toxicity than anti-PD-1 (RR: 0.33, 95%CI: 0.14-0.77), anti-PD-L1 (RR: 0.38, 95%CI:0.16-0.91), and anti-PD-1 plus anti-CTLA-4 (RR: 0.32, 95%CI: 0.12-0.87) in terms of grade 3-5 RAEs. The difference was not significant between ICI monotherapy and traditional cancer therapy, except that targeted therapy seemed the least toxic therapy in terms of the incidence of AKI. Anti-CTLA-4 plus anti-PD-1 were associated with higher risk of RAEs than anti-PD-1 (RR: 1.61, 95%CI: 1.02-2.56). The difference was not significant between other dual ICI regimens and ICI monotherapy in terms of RAEs and AKI. ICI plus chemotherapy showed increased risk of both RAEs and AKI compared with ICI monotherapy, chemotherapy, and targeted therapy. The overall results remained robust in the meta-regression and sensitivity analyses.

Conclusions

Among ICI monotherapy, anti-CTLA-4 appeared to be associated with increased toxicity, especially in terms of grade 3-5 RAEs. Anti-CTLA-4 plus anti-PD-1 were associated with higher risk of RAEs than anti-PD-1. However, the difference was not significant between other dual ICI regimens and ICI monotherapy in terms of RAEs and AKI. ICIs plus chemotherapy seemed to be the most toxic treatment regimen in terms of RAEs, AKI, and grade 3-5 AKI.

Systematic review registration

PROSPERO, identifier CRD42020197039.

SUBMITTER: Liu K

PROVIDER: S-EPMC8242344 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

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.

Project description:Unlabelled: In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended.Implications for practiceImmune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer. Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be life-threatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed.

Project description:Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15-60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity.Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs.MethodsWe performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate.ResultsMost patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not.ConclusionWe found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings.Implications for practiceThis study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

Project description:ImportanceSince 2011, immune checkpoint inhibitors (ICIs) have been effective treatment options for advanced melanoma. Little is known about how risks of immune-related adverse events (irAEs) vary by ICIs.ObjectiveTo compare the risk of irAEs across different treatment regimens for advanced melanoma using network meta-analysis.Data sourcesPubMed/MEDLINE, Embase, Web of Science, and Scopus were searched for all randomized clinical trial (RCT) articles published from January 1, 2010, through June 30, 2019.Study selectionStudies included phases 2 and 3 RCTs in the treatment of advanced melanoma that compared ICIs (ipilimumab, nivolumab, and pembrolizumab) with chemotherapy drugs (eg, dacarbazine, carboplatin, and paclitaxel) or different ICI regimens.Data extraction and synthesisDifferent treatment regimens were compared using bayesian network meta-analysis with Markov chain Monte Carlo simulation with noninformative prior distribution and random-effects generalized linear models.Main outcomes and measuresPrimary outcomes were the cumulative incidence of any irAEs (regardless of severity) and severe irAEs (grades 3-5). Based on the pooled odds ratios (ORs) and 95% credible intervals (95% CrI), the probability of being associated with the lowest irAE risks was estimated for each treatment regimen.ResultsNine RCTs with 8 different treatment regimens for advanced melanoma and involving a total of 5051 patients were included. Overall, the 3 ICI treatment regimens associated with the lowest risk of any or severe irAEs were pembrolizumab, 2 mg/kg, every 3 weeks; nivolumab, 3 mg/kg, every 2 weeks; and pembrolizumab, 10 mg/kg, every 3 weeks. Compared with ipilimumab, 10 mg/kg, every 3 weeks, only nivolumab, 3 mg/kg, every 2 weeks, was associated with a decreased risk for any irAEs (OR, 0.34; 95% CrI, 0.13-0.94). A decreased risk for severe irAEs was observed for ipilimumab, 3 mg/kg, every 3 weeks (OR,?0.35; 95% CrI,?0.14-0.74); pembrolizumab, 10 mg/kg, every 2 weeks (OR,?0.22; 95% CrI,?0.05-0.95) and 10 mg/kg every 3 weeks (OR,?0.20; 95% CrI,?0.06-0.68); and nivolumab, 3 mg/kg, every 2 weeks (OR,?0.20; 95% CrI,?0.07-0.48) compared with ipilimumab, 10 mg/kg, every 3 weeks. An increased risk for severe irAEs was associated with nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks compared with other ICI regimens (ORs ranging from?4.09 [95% CrI, 1.73-10.99] to 7.40 [95% CrI, 1.12-49.29]) except ipilimumab, 10 mg/kg, every 3 weeks.Conclusions and relevanceThese findings suggest that for patients with advanced melanoma at high risk of irAEs, pembrolizumab, 2 mg/kg, every 3 weeks, nivolumab, 3 mg/kg, every 2 weeks, and pembrolizumab, 10 mg/kg, every 3 weeks may be the preferred treatment regimens (with respect to irAE risks) among the ICI regimens reported, whereas ipilimumab, 10 mg/kg, every 3 weeks alone and nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks should be used with caution. A network analysis may be valuable for clinical decision-making when evidence from head-to-head comparisons is lacking.