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Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis.

ABSTRACT: Purpose:We performed this systematic review and meta-analysis to assess the incidence of fatal adverse events that were associated with the use of programmed cell death ligand 1 (PD-L1) inhibitors, to describe them and to statistically depict factors that were associated with these events. Method:PubMed, Embase, and Cochrane Library were completely searched based on the following terms or relevant Medical Subject Heading ones: "atezolizumab", "durvalumab", "avelumab", and "cemiplimab". Results:A total of 26 eligible studies were identified, incorporating 6,896 unique participants. The overall incidence was 1.24% (95% CI: 0.93-1.65%). The incidence and odds were higher in patients with non-squamous non-small cell lung cancer (NSCLC) than those with urothelial carcinoma [(2.25 vs. 0.85, p = 0.04), (odds ratio [OR]: 2.69; 95% CI: 1.04-6.97, p = 0.04)], higher in the middle-aged group than the young group [(1.74 vs. 0.89, p = 0.01), (OR: 2.13; 95% CI: 1.26-3.61, p = 0.01)], and higher in the trial phase I than the trial phase II [(1.76 vs. 0.60, p = 0.01), (OR: 0.31; 95% CI: 0.13-0.75, p = 0.01)]. Notably, the trial phase I had a higher incidence than trial phase II or III following regulating for cancer types and average age (OR: 0.28; 95% CI: 0.11-0.71, p = 0.01, OR: 0.48; 95% CI: 0.24-0.95, p = 0.04, respectively). In terms of organ-specific fatal adverse events, interstitial lung disease (ILD) was frequently documented. A variety of respiratory system-related fatal adverse events were recorded, including but not limited to pneumonia and respiratory failure. As for organ-unspecific fatal adverse events, substantial cases of sepsis and neutropenia were recorded. Conclusion:This study firstly provided a comprehensive incidence and the spectrum of fatal adverse events associated with PD-L1 inhibitors, and identified three potential susceptible factors of that, yielding a capability for clinicians to distinguish high-risk populations from relatively low-risk ones, and facilitating to improve the safety of PD-L1 inhibitors broadly used in the clinical setting.

SUBMITTER: Wang X

PROVIDER: S-EPMC7006642 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis.

Wang Xuewen X Wu Shijie S Chen Yaying Y Shao Erqian E Zhuang Tingting T Lu Linbin L Chen Xiong X

Frontiers in pharmacology 20200131

<h4>Purpose</h4>We performed this systematic review and meta-analysis to assess the incidence of fatal adverse events that were associated with the use of programmed cell death ligand 1 (PD-L1) inhibitors, to describe them and to statistically depict factors that were associated with these events.<h4>Method</h4>PubMed, Embase, and Cochrane Library were completely searched based on the following terms or relevant Medical Subject Heading ones: "atezolizumab", "durvalumab", "avelumab", and "cemipli ...[more]

PMID: 32076409

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Project description:BackgroundProgrammed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.MethodsArticles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.ResultsSixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved.ConclusionsThe specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

Project description:IntroductionProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings.MethodsExtensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis.ResultsTen nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1-21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3-14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9-27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5-2.9 vs. 2.0-2.7 months and 7.9-18.2 vs. 15.9 months) and second-line chemotherapy (3.3-4.0 months and 7.4-8 months). Odds of achieving ORR was 0.10 (95% CI 0.03-0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19-0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible.ConclusionsPD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.

Project description:ImportanceImmune checkpoint inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment. Understanding the clinical efficacy and safety profile of these drugs is necessary for treatment strategy in clinical practice.ObjectiveTo assess the differences between anti-PD-1 and anti-PD-L1 regarding efficacy and safety shown in randomized clinical trials across various tumor types.Data sourcesSystematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to March 1, 2019. In addition, abstracts and presentations from all major conference proceedings were reviewed.Study selectionAll randomized clinical trials that compared anti-PD-1 and anti-PD-L1 with standard treatment in patients with cancer were selected as candidates. Retrospective studies, single-arm phase 1/2 studies, and trials comparing anti-PD-1 and anti-PD-L1 with other immunotherapies were excluded. Studies of anti-PD-1 and anti-PD-L1 therapy were screened and paired by the matching of clinical characteristics as mirror groups.Data extraction and synthesisThree investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Trial names, first author, year of publication, study design, National Clinical Trial identifier number, blinding status, study phase, pathologic characteristics, number of patients, patients' age and sex distribution, Eastern Cooperative Oncology Group Performance Status, lines of treatment, study drugs, biomarker status, follow-up time, incidence of adverse events, and hazard ratios (HRs) with 95% CIs for overall survival and progression-free survival were extracted. A random-effects model was applied for data analysis.Main outcomes and measuresDifferences in OS between anti-PD-1 and anti-PD-L1 across different cancer types were assessed. An effect size was derived from each mirror group and then pooled across all groups using a random-effects model.ResultsNineteen randomized clinical trials involving 11 379 patients were included in the meta-analysis. Overall, anti-PD-1 exhibited superior overall survival (HR, 0.75; 95% CI, 0.65-0.86; P < .001) and progression-free survival (HR, 0.73; 95% CI, 0.56-0.96; P = .02) compared with anti-PD-L1. No significant difference was observed in their safety profiles. Sensitivity analysis presented consistency in the overall estimates across these analyses. Consistent results were observed through frequentist and bayesian approaches with the same studies.Conclusions and relevanceComprehensive analysis suggests that anti-PD-1 exhibited favorable survival outcomes and a safety profile comparable to that of anti-PD-L1, which may provide a useful guide for clinicians.

Dataset Information

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis.

Publications

Fatal Adverse Events Associated With Programmed Cell Death Ligand 1 Inhibitors: A Systematic Review and Meta-Analysis.

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