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Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis.

ABSTRACT: OBJECTIVE:To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments. DESIGN:Systematic review and meta-analysis. DATA SOURCES:Medline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials.gov. STUDY SELECTION:Eligible studies included primary clinical trial data on patients with cancer with recurrent or metastatic disease. DATA EXTRACTION:Three independent investigators extracted data on adverse events from ClinicalTrials.gov and the published studies. Risk of bias was assessed using the Cochrane tool by three independent investigators. RESULTS:13 relevant studies were included; adverse event data were available on ClinicalTrials.gov for eight. Studies compared nivolumab (n=6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain. CONCLUSIONS:Organ specific immune-related adverse events are uncommon with anti-PD-1 drugs but the risk is increased compared with control treatments. General adverse events related to immune activation are largely similar. Adverse events consistent with musculoskeletal problems are inconsistently reported but adverse events may be common.

SUBMITTER: Baxi S

PROVIDER: S-EPMC5851471 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis.

Baxi Shrujal S Yang Annie A Gennarelli Renee L RL Khan Niloufer N Wang Ziwei Z Boyce Lindsay L Korenstein Deborah D

BMJ (Clinical research ed.) 20180314

<h4>Objective</h4>To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments.<h4>Design</h4>Systematic review and meta-analysis.<h4>Data sources</h4>Medline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials. ...[more]

PMID: 29540345

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Project description:ObjectiveWe aimed to evaluate immune-related adverse events occurring in clinical trials of anti-programmed cell death 1 (PD-1) drugs, compared with control treatments, including chemotherapy, targeted drugs, or placebo. Further we compared the occurrence of immune -related events in patients treated with different anti-PD-1 drugs.Data sourcesRandomized controlled trial (RCT) data were sourced from PubMed, Embase, and the Cochrane Central Register of Controlled Trials combined with https://clinicaltrials.gov.MethodsRandomized controlled trial of anti-PD-1 drugs compared with control treatments published between January 1, 1970 and March 1,2019, were searched and data on trial patient characteristics, and adverse events extracted, reviewed, and subjected to meta-analysis.ResultsEighteen Randomized controlled trials were included in our study. The Randomized controlled trials compared nivolumab (n = 12), pembrolizumab (n = 6), with chemotherapy (n = 13), targeted drugs (n = 2), or placebo (n = 3). Compared with the control group, the risk of any immune-related adverse events in patients treated with anti-PD-1 drugs was increased (RR, 2.65; 95% confidence interval, 1.84-3.83; P < 0.00001). Of the immune-related adverse events, the risk rates of pneumonitis (risk ratio, 2.10; 95% CI, 0.85-5.18), colitis (2.96;1.62-5.38), hypophysitis(4.79;1.54-14.89), hypothyroidism(7.87;5.36-11.57), hyperthyroidism (7.03;4.35-11.34), rash (1.58;0.98-2.54), pruritus (2.28; 1.38-3.76), and hepatitis (9.31;2.18-39.85) were increased by anti-PD-1 drugs. Further, the risk of immune-related adverse events was similar for patients treated with pembrolizumab and nivolumab (P = 0.14).ConclusionsIn addition to previously reported organ-specific immune-related adverse events, we found that the risk of hyperthyroidism was also increased, in anit-PD-1-treated patients, relative to control treatments. The risk of total immune-related adverse events, was similar for pembrolizumab and nivolumab.

Project description:to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors. randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science from 1 January 2019 to 31 May 2021. Adverse events data were extracted from clinical trials website or original article by two authors separately. Meta-analysis was used to determine risk ratio (RR) and 95% confidence interval (95% CI) of adverse events in PD-1/PD-L1 inhibitors groups compared to that of control groups. Subgroup analyses were also performed. a total of 5,807 studies were initially identified and after exclusion, 41 studies were included in meta-analysis. All the trials were international multicenter, randomized, phase II/III clinical trials, with the median follow-up of 27.5 months on average. Analysis of all grade adverse events showed that PD-1/PD-L1 inhibitors treatment significantly increased the risk of immune-related adverse events, including pruritus (RR: 2.34, 95% CI: 1.85-2.96), rash (RR: 1.53, 95% CI: 1.25-1.87), ALT elevation (RR 1.54, 95% CI 1.23-1.92), AST elevation (AST: RR 1.49, 95% CI 1.20-1.85), hepatitis (RR: 3.54, 95% CI: 1.96-6.38) and hypothyroid (RR: 5.29, 95% CI: 4.00-6.99) compared with that of control group. Besides that, PD-1/PD-L1 inhibitors were associated with higher risk of adverse events related to respiratory system including cough (RR: 1.33, 95% CI: 1.21-1.48), dyspnea (RR:1.23, 95% CI: 1.12-1.35) and chest pain (RR: 1.26, 95% CI: 1.07-1.47) compared with that of control groups in our meta-analysis and the dyspnea was taken high risk both in all grade and grade 3 or higher (RR: 1.55, 95% CI: 1.13-2.12). The risk of arthralgia was increased with PD-1/PD-L1 inhibitors (RR: 1.27, 95% CI: 1.10-1.47). Although the risk of myalgia was similar with PD-1/PD-L1 inhibitors and control groups, under subgroup analysis, PD-1/PD-L1 inhibitors decreased the risk of myalgia (RR: 0.56, 95% CI: 0.45-0.70) compared with that of chemotherapy. our results provide clear evidence that the risk of treatment-related adverse events in PD-1 or PD-L1 varies widely in different system. In particular, when using PD-1/PD-L1 inhibitors for oncology treatment, besides the common immune-related adverse events like pruritus, rash, hepatitis, and hypothyroid, the respiratory disorders and musculoskeletal disorders, such as cough, dyspnea, arthralgia, and myalgia, should also be taken into consideration.

Project description:ImportanceProgrammed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice.ObjectiveTo evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.Data sourcesPubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.Study selectionPublished clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.Data extraction and synthesisTrial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.Main outcomes and measuresIncidences of treatment-related adverse events and differences between different drugs and cancer types.ResultsThis systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).Conclusions and relevanceDifferent PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

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.

Dataset Information

Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis.

Publications

Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis.

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