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Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.

ABSTRACT: BACKGROUND:A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial. METHODS:Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed. RESULTS:This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45-0.65; p?

SUBMITTER: Zhou X

PROVIDER: S-EPMC7169020 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.

Zhou Xiaoxiang X Yao Zhuoran Z Yang Huaxia H Liang Naixin N Zhang Xuan X Zhang Fengchun F

BMC medicine 20200420 1

<h4>Background</h4>A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial.<h4>Methods</h4>Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and effica ...[more]

PMID: 32306958

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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: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.

Project description:BackgroundImmune Checkpoint Inhibitors (ICI) have been progressively used in cancer treatment and produced unique toxicity profiles. This systematic review aims to comprehend the patterns and occurrence of treatment-related adverse events (trAEs) based on ICI.MethodsPICOS/PRISMA methods were used to identify published English-language on PubMed, Web of Science, and Scopus from 2015 to 2020. Published clinical trials on ICI monotherapy, combined ICIs, and ICI plus other treatment with tabulated data on grade≥3 trAEs were included. Odds ratio (OR), χ2 tests were used to analyze for effect size and associations.ResultsThis review included 145 clinical trials involving 21786 patients. Grade 3-5 trAEs were more common with ICI when they were plused with other treatments compared with ICI monotherapy(54.3% versus 17.7%, 46.1%, p<0.05). Grade 3-5 trAEs were also more common with CTLA-4 mAbs compared with anti-PD-1 and anti-PD-L1 (34.2% versus 15.1%, 13.6%, p<0.05). Hyperthyroidism (OR 3.8, 95%CI 1.7-8.6), nausea (OR 3.7, 95%CI 2.5-5.3), diarrhea (OR 2.7, 95%CI 2.2-3.2), colitis (OR 3.4, 95%CI 2.7-4.3), ALT increase (OR 4.9, 95%CI 3.9-6.1), AST increase (OR 3.8, 95%CI 3.0-4.9), pruritus (OR 2.4, 95%CI 1.5-3.9), rash (OR 2.8, 95%CI 2.1-3.8), fatigue (OR 2.8, 95%CI 2.2-3.7), decreased appetite (OR 2.4, 95%CI 1.5-3.8), and hypophysitis (OR 2.0, 95%CI 1.2-3.3) were more frequent with combined ICIs. Diarrhea (OR 8.1, 95%CI 6.4-10.3), colitis (OR 12.2, 95%CI 8.7-17.1), ALT increase (OR 5.1, 95%CI 3.5-7.4), AST increase (OR 4.2, 95%CI 2.8-6.3), pruritus (OR 4.1, 95%CI 2.0-8.4), rash (OR 4.4, 95%CI 2.9-6.8), hypophysitis (OR 12.1, 95%CI 6.3-23.4) were more common with CTLA-4 mAbs; whereas pneumonitis (OR 4.7, 95% CI 2.1-10.3) were more frequent with PD-1 mAbs.ConclusionsDifferent immune checkpoint inhibitors are associated with different treatment-related adverse events profiles. A comprehensive data in this systematic review will provide comprehensive information for clinicians.

Project description:ObjectivesImmune checkpoint inhibitors (ICIs) have brought impressive benefits to cancer patients, however often accompanied with immune-related adverse events (irAEs). We aimed to investigate the association of irAEs with efficacy and overall survival in cancer patients treated by ICIs, and further quantify the association by stratifying subgroups.MethodsPubMed, EMBASE and Cochrane library from database inception to 29 August 2019 were systematically searched. Articles reporting association of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) with irAEs in cancer patients treated with approved ICIs were included. Adjusted odds ratios (OR) with 95% confidential intervals (CIs) were calculated for ORR, and hazard ratios (HR) were used for PFS and OS.ResultsA total of 52 articles comprising 9,156 patients were included. Pooled data demonstrated a statistically significant greater probability of achieving objective tumor response for patients with irAEs compared to those without (OR 3.91, 95% CI 3.05-5.02). In overall meta-analysis, patients who developed irAEs presented a prolonged PFS (HR 0.54; 95% CI 0.46-0.62) and OS (HR 0.51; 95% CI 0.41-0.59). More specifically, irAEs in certain cancer types (NSCLC and melanoma) and organs (skin and endocrine) were robustly associated with better clinical outcomes, while this association needs further verification regarding other tumors. High grade toxicities (G3-5) were not associated with a significantly favorable PFS or OS. Additionally, the association between irAEs and clinical benefit seemed to be more definite in patients receiving PD-(L)1 blockade than CTLA-4 blockade. Pooled data from landmark analyses displayed consistent results.ConclusionsThe occurrence of irAEs predicted improved tumor response and better survival in overall cancer patients treated with ICIs. Notably, the association stayed robust in certain cancer types (NSCLC and melanoma) and organ-specific irAEs (skin and endocrine).

Project description:Background: Immune checkpoint blockade has revolutionized the treatment of multiple malignancies. Currently, however, the effect is not universal, with objective response rates (ORR) of about 15-25%, and even lower for some cancers. Abnormal vasculature is a hallmark of most solid tumors and plays a role in immune evasion. Growing body of evidence suggests that vascular normalization and immune reprogramming could operate synergistic effect, resulting in an enhanced therapeutic efficacy. However, the benefit of antitumor efficacy must be weighed against the risk of added toxicity. In this systematic review, we summarize severe toxicity observed in such a kind of combination regimen. Methods: PubMed and Embase were searched for English references published up to May 31, 2019, with MeSH and keywords search terms of immune checkpoint inhibitors (ICIs) and antiangiogenic agents approved for using in solid tumors. Studies performing concomitant use of ICIs and antiangiogenic agents, and also reporting severe treatment-related adverse events (trAEs) (?grade 3), were included for further analysis. Results: A total of 32 studies including a total of 2,324 participants were analyzed. Limited available data suggests that both antiangiogenic monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) show potential risk of increasing treatment-related toxicity when combined with ICIs. Overall, the total incidence of severe adverse events (AEs) associated with ICIs plus mAbs (44.5%) is lower than that of ICIs plus TKIs (60.1%). However, the trAEs observed in combination therapy are mostly consistent with the known safety profiles of corresponding monotherapy, and they seem to be largely related to antiangiogenic agents, rather than a true immune-related adverse event (irAE) predominantly due to ICIs. The majority of trAEs are intervened by holding ICI treatment and adding corticosteroids, as well as reducing dose or adjusting administration frequency of the antiangiogenic drugs. Conclusions: Concurrent use of ICIs and antiangiogenic agents shows potential treatment-related toxicity. Further research is required to compare the efficacy and safety of the combination regimen and corresponding monotherapy and identify predictive biomarkers, as well as explore dose, duration, and sequencing schedules of drugs.

Dataset Information

Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.

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Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis.

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