The effect of adding immune checkpoint inhibitors on the risk of pneumonitis for solid tumours: a meta-analysis of phase III randomised controlled trials

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p<0.001 and HR 0.77, p<0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p<0.012), with the exception of melanoma (in women, HR 0.80, p=0.006). PFS was longer in men than in women (HR 0.67, p<0.001 and HR 0.77, p=0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.

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Efficacy and safety of immune checkpoint inhibitors in gastric cancer: a network meta-analysis of well-designed randomized controlled trials

Annals of Translational Medicine ◽

10.21037/atm-20-6639 ◽

2021 ◽

Vol 9 (4) ◽

pp. 290-290

Author(s):

Siwei Pan ◽

Kai Li ◽

Baojun Huang ◽

Jinyu Huang ◽

Huimian Xu ◽

...

Keyword(s):

Gastric Cancer ◽

Randomized Controlled Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Controlled Trials ◽

Efficacy And Safety ◽

Randomized Controlled

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Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour

BMJ Open ◽

10.1136/bmjopen-2017-017240 ◽

2018 ◽

Vol 8 (9) ◽

pp. e017240 ◽

Cited By ~ 9

Author(s):

Jianrong Zhang ◽

Yiyin Zhang ◽

Shiyan Tang ◽

Long Jiang ◽

Qihua He ◽

...

Keyword(s):

Literature Review ◽

Correlation Analysis ◽

Randomised Controlled Trials ◽

Treatment Effects ◽

Solid Tumours ◽

Phase Iii ◽

Controlled Trials ◽

Systematic Bias ◽

Randomised Controlled ◽

Local Assessment

ObjectiveUnbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments.DesignLiterature review, pooling analysis and correlation analysis.Data sourcesPubMed, from 1 January 2010 to 30 June 2017.Eligibility criteria for selecting studiesEligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments.ResultsOf 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29).ConclusionsNo systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.

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Cardiovascular toxicity incidence following immune checkpoint inhibitors in randomized clinical trials: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2636 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2636-2636

Author(s):

Camila Bragança Xavier ◽

Carlos Diego Holanda Lopes ◽

Guilherme Harada ◽

Artur Katz ◽

Denis Leonardo Fontes Jardim

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Randomized Clinical Trials ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Best Supportive Care ◽

Phase Iii ◽

Increased Risk ◽

Meta Analyses

2636 Background: Immune checkpoint inhibitors (ICIs) are widely used in oncology and may be associated with a variety of immune-related toxicities. Cardiovascular (CV) adverse effects (AEs) are underreported in randomized clinical trials (RCTs), and the real risk associated with ICIs use has yet to be defined. Therefore, we aimed to investigate the incidence and risk of cardiovascular toxicities in patients receiving ICIs, using an up-to-date meta-analysis of prospective RCTs. Methods: We conducted a systematic search of the literature from January 1st, 2010 until July 1st, 2020 to identify RCTs testing ICIs for solid tumors, either in monotherapy or in combination between them. Our initial search yielded a total of 21,249 relevant publications. For CV AEs incidence estimation, we included phase III RCTs testing PD-1, PD-L1, CTLA-4 inhibitors or any combination of these agents. For relative risk (RR) assessment, we included phase II or phase III RCTs testing the same agents and with placebo or best supportive care (BSC) as the comparator. Data were extracted by independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. CV AEs were categorized based on the Common Toxicity Criteria (CTCAE) and stratified by ICIs type. Analyses were conducted using random effects model. Results: After screening and eligibility assessment, a total of 21,118 patients (67 cohorts from 57 trials) were available for this meta-analysis. We categorized the cohorts by ICIs regimen as monotherapy with a PD-1 inhibitor (35 cohorts; 10,241 patients), PD-L1 inhibitor (12 cohorts; 3,755 patients), CTLA-4 inhibitor (11 cohorts; 4,135 patients), and combination therapy (9 cohorts; 2,987 patients). Incidence measures are described in the table. Deaths from any CV cause occurred in 0.20% of the patients (95%CI 0.10%; 0.20%). For RR analysis, we included 12 cohorts from 11 RCTs. Risk of experiencing all grade AEs was numerically higher among patients who received ICIs than placebo or BSC (RR 1.16; 95%CI 0.98; 1.37; p=0.09). When only grade 3-5 CV AEs were considered, ICIs were associated with increased risk (RR 1.36; 95%CI 1.06; 1.73; p= 0.01). Additional analyses were conducted to estimate the RR of individual CV AEs including arrhythmia, cardiac arrest, heart failure, stroke, hypertension, myocardial infarction, myocarditis, pericardial events, and thromboembolic events. None of the analysis identified a significant additional risk. Conclusions: This meta-analysis corroborates the preclinical rationale of worsen CV risk related to ICIs use.[Table: see text]

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Is there a benefit of immune checkpoint inhibitors for patients over 75 years of age with advanced cancer in first and second line setting: A meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.12031 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 12031-12031 ◽

Cited By ~ 1

Author(s):

Thierry Landre ◽

Gaetan Des Guetz ◽

Christos Chouaid ◽

Jean F. Morere ◽

Kader Chouahnia ◽

...

Keyword(s):

Cell Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Phase Iii ◽

Second Line ◽

First Line ◽

Line Setting ◽

The Impact

12031 Background: The impact of aging on Immune Checkpoint Inhibitors (ICIs) effectiveness is controversial. Currently, data from clinical studies do not show any difference between patients over 65 years and those under 65 years. We propose to compare the clinical benefit of ICIs in those over 75 and in those under 75. Methods: We performed a meta-analysis of published randomized control trials (RCTs) concerning ICIs versus standard therapy in patients with advanced solid tumours. Overall Survival (OS) among the older (≥75 years) was compared with that of younger patients ( < 75 years) in first and second line setting. Hazard ratios (HRs) with their 95% confidence interval (CI) were collected from the studies and pooled. Results: Fifteen phase III studies evaluating anti-PD-1 (nivolumab or pembrolizumab), anti-PD-L1 (atezolizumab or avelumab) or anti-CTLA-4 (ipilimumab) were included. Patients were enrolled for Non-Small-Cell-Lung-Cancer, Renal-Cell-Carcinoma, Melanoma, Head-and-Neck-Squamous-Cell-Carcinoma or Gastric-Cancer. Eight studies assessed treatment in first line setting and seven in second line. The median age was 64 years, with 906 patients over 75 years of age and 5233 younger. In first line setting, HRs for death were 0.78 (95% CI: 0.61-0.99) in patients ≥75 years versus 0.84 (95% CI: 0.71-1.00) in younger. In second line setting, HRs for death were 1.02 (95% CI: 0.77-1.36) in patients ≥75 years versus 0.68 (95% CI: 0.61-0.75) in younger with a statistically significant difference observed between subgroups (p interaction = 0.009). Conclusions: ICIs appears to be effective in patients over 75 years of age. However, the survival benefit comes mainly from the first line of treatment. This result encourages the use of ICIs early in the therapeutic management of patients over 75 years of age.

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A systematic review and network meta-analysis of phase III randomised controlled trials for adjuvant therapy following resection of pancreatic ductal adenocarcinoma (PDAC)

HPB ◽

10.1016/j.hpb.2019.12.001 ◽

2020 ◽

Vol 22 (5) ◽

pp. 649-659 ◽

Cited By ~ 2

Author(s):

Sivesh K. Kamarajah ◽

James R. Bundred ◽

Wasfi Alrawashdeh ◽

Derek Manas ◽

Steven A. White

Keyword(s):

Systematic Review ◽

Adjuvant Therapy ◽

Pancreatic Ductal Adenocarcinoma ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Controlled Trials ◽

Randomised Controlled

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Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

Pharmaceuticals ◽

10.3390/ph14050476 ◽

2021 ◽

Vol 14 (5) ◽

pp. 476

Author(s):

Alberto Bongiovanni ◽

Brigida Anna Maiorano ◽

Irene Azzali ◽

Chiara Liverani ◽

Martine Bocchini ◽

...

Keyword(s):

Systematic Review ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Phase Iii ◽

Neuroendocrine Neoplasms ◽

Phase Ii Trials

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28–56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.

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