The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis

Abstract Background Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI. Methods A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies. Results After screening 1145 abstracts, fifteen observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9-10.2 months. In the non-steroid group, median OS ranged from 4.9-25.1 months. Pooled results demonstrated significantly worse OS (HR 1.84, 95% CI 1.22-2.77) and systemic progression free survival (PFS; HR 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR 1.31, 95% CI 0.42-4.07). Conclusions Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

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72. THE COMBINED USE OF STEROIDS AND IMMUNE CHECKPOINT INHIBITORS IN BRAIN METASTASES PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa073.059 ◽

2020 ◽

Vol 2 (Supplement_2) ◽

pp. ii15-ii15

Author(s):

Charissa Jessurun ◽

Alexander Hulsbergen ◽

Anouk de Wit ◽

Ishaan Ramlochan Tewarie ◽

Marike Broekman

Keyword(s):

Systematic Review ◽

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Significant Heterogeneity ◽

Tumor Type ◽

Random Effects Models ◽

Steroid Group

Abstract INTRODUCTION Immune checkpoint inhibitors (ICI) are increasingly being administered to cancer patients, including those with brain metastases (BMs). However, little is known about the interaction between ICI and steroids such as dexamethasone. The aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI. METHODS A systematic literature search was performed in PubMed, Embase, Web of Science, Cochrane, Academic Search Premier, and PsycINFO. Pooled effect estimates were calculated using random-effects models; analysis was performed across all included studies and stratified by tumor type. RESULTS After screening 978 abstracts, thirteen studies were included for systematic review. Ten studies reported sufficient data for meta-analysis, comprising 838 BM patients of which 335 (40%) had received steroids. In the steroid group, median OS ranged from 2.9 months to 10.2 months across studies. In the non-steroid group, median OS ranged from 4.9 to 25.1 months. Pooling results demonstrated significantly worse survival in the steroid group (HR 1.97; 95% CI 1.65–2.36); no significant heterogeneity (I2 = 0%) or publication bias (Egger’s p = 0.29) was identified. Stratified analysis showed a consistent effect across melanoma (HR 1.71, 95% CI 1.34–2.18) and non-small cell lung cancer (HR 2.26, 95% CI 1.49–3.43) subgroups. CONCLUSION Administration of steroids is associated with a significantly worse OS in BM patients receiving ICI. Further investigation on dose, timing and duration of steroids in this population is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

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Immune-checkpoint inhibitors versus other systemic therapies in advanced head and neck cancer: a network meta-analysis

Immunotherapy ◽

10.2217/imt-2020-0070 ◽

2021 ◽

Vol 13 (6) ◽

pp. 541-555

Author(s):

Lingrong Tang ◽

Tingting Liu ◽

Jun Chen ◽

Jun Dang ◽

Guang Li

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Systemic Therapies

Aim: We assessed the efficiency of immune checkpoint inhibitors relative to other systemic therapies in previously treated recurrent/metastatic head and neck cancer. Materials & methods: Relative treatment effects were assessed from eligible randomized controlled trials using Bayesian network meta-analyses. Results: Among 15 trials evaluating 14 treatments, nivolumab achieved the best overall survival (OS) benefit; zalutumumab and buparlisib + paclitaxel provided the best progression-free survival benefit and objective response rate. Buparlisib + paclitaxel and zalutumumab were associated with the best OS rate at 6 and 12 months, respectively; nivolumab yielded the best OS rate at 18–24 months. Conclusion: Nivolumab was the most favorable treatment. Zalutumumab and buparlisib + paclitaxel had better efficiency, and might be a better selection for patients with programmed death-ligand 1-low/negative tumors than other treatments.

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Immune checkpoint inhibitors and chemotherapy in first-line NSCLC: a meta-analysis

Immunotherapy ◽

10.2217/imt-2020-0224 ◽

2021 ◽

Author(s):

Fausto Petrelli ◽

Roberto Ferrara ◽

Diego Signorelli ◽

Antonio Ghidini ◽

Claudia Proto ◽

...

Keyword(s):

Immune Checkpoint ◽

Evaluation System ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

First Line ◽

Random Effects Models ◽

Assessment Development ◽

Programmed Death ◽

Quantitative Synthesis

This study is a meta-analysis of randomized controlled trials involving first-line studies in which immune checkpoint inhibitors were added to chemotherapy and were compared with chemotherapy alone. The primary end point was overall survival (OS). The analyses used random-effects models and the Grading of Recommendations Assessment, Development, and Evaluation system to rate the quality of the evidence. Nine articles were included for qualitative and quantitative synthesis. A meta-analysis of the nine randomized trials showed a significant benefit in terms of OS (hazard ratio: 0.75 [95% CI: 0.66–0.85]; p < 0.01). Only programmed death ligand-1 positive-high cancers derive a significant OS benefit. In this meta-analysis, there is moderate evidence that the addition of immune checkpoint inhibitors to chemotherapy may improve both OS compared with chemotherapy alone.

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Comparison of RECIST 1.1 and iRECIST in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Cancers ◽

10.3390/cancers13010120 ◽

2021 ◽

Vol 13 (1) ◽

pp. 120

Author(s):

Hyo Jung Park ◽

Gun Ha Kim ◽

Kyung Won Kim ◽

Choong Wook Lee ◽

Shinkyo Yoon ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Recist 1.1 ◽

Rate Ratios ◽

A Minor ◽

Survival Endpoint ◽

The Impact

Despite wide recognition of iRECIST, evidence regarding the impact of iRECIST over RECIST 1.1 is lacking. We aimed to evaluate the impact of iRECIST on assessing treatment efficacy of immune checkpoint inhibitors (ICIs) over RECIST 1.1. Articles that evaluated the treatment response and outcome based on both RECIST 1.1 and iRECIST were eligible. Data regarding overall response rates (ORR) and disease control rate (DCR) based on RECIST 1.1 and iRECIST, and data required to estimate individual patient data of progression-free survival (PFS) were extracted. Estimates were compared using meta-regression and pooled incidence rate ratios. The pooled difference of restricted mean survival time (RMST) of PFS between two criteria were calculated. Eleven studies with 6210 patients were analyzed. The application of iRECIST had no impact on the response-related endpoint by showing no significantly different ORR and DCR from RECIST 1.1 (pooled ORR, 23.6% and 24.7% [p = 0.72]; pooled DCR, 45.3% and 48.7% [p = 0.56] for iRECIST and RECIST 1.1, respectively) and had a minor impact on a survival endpoint by showing longer RMST of PFS than RECIST 1.1 (pooled difference, 0.46 months; 95% CI, 0.10–0.82 months; p = 0.01). Such a modest benefit of iRECIST should be considered when we design a clinical trial for immune checkpoint inhibitors.

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191. The impact of antibiotic use on clinical outcomes in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.235 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S101-S101

Author(s):

Maria Tsikala Vafea ◽

Neel Belani ◽

Kendra Vieira ◽

Dimitrios Farmakiotis

Keyword(s):

Cancer Patients ◽

Clinical Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Antibiotic Use ◽

Experimental Models ◽

The Impact

Abstract Background Observational studies and experimental models suggest that use of antibiotics close to the administration of immune checkpoint inhibitors (ICI) can negatively affect tumor response and patient survival. This observation may be attributed to microbiome dysbiosis and the resultant suppression of host immune response against neoplastic cells. Methods We conducted a systematic search of PUBMED and EMBASE databases and references of articles retrieved. We included studies published between 1/1/17 and 2/1/20, which evaluated the association between antibiotic use and clinical outcomes in cancer patients treated with ICI. Primary endpoints were overall survival (OS), progression free survival (PFS), response rate (RR) and progressive disease (PD) rate. We performed a study-level random-effects meta-analysis with pooling of hazards ratios (HR) for OS, PFS, and odds ratios (OR) for RR and PD (PROSPERO ID: CRD42020166473). Results We included 41 studies with a total of 10,857 patients. The most common malignancies were lung cancer (59.7%), melanoma (23.1%), renal cell and urothelial carcinomas (8.1%). OS and PFS were shorter, RR lower, and PD higher in patients receiving antibiotics, both in univariate analyses and after adjustment for other confounders. Heterogeneity was significant for all outcomes, less so for adjusted OS and PFS (Table). To our knowledge, this is the largest meta-analysis on the association between antibiotic use and efficacy of ICI, and the only one to address RR and PD to-date. Association between antibiotics and clinical outcomes. Conclusion We demonstrated a significant association between antibiotic use and unfavorable clinical outcomes in patients with cancer receiving ICI. Such patients may be an important target group for antibiotic stewardship interventions. The high heterogeneity across all outcomes underscores the need for more detailed, patient-level studies with stratification by host, antibacterial and cancer treatment factors. Disclosures All Authors: No reported disclosures

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Impact of corticosteroids use on efficacy of immune checkpoint inhibitors in cancer patients: A meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15234 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15234-e15234

Author(s):

Jiarui Li ◽

Kaili Yang ◽

Lin Zhao ◽

Chunmei Bai ◽

Zhao Sun

Keyword(s):

Cancer Patients ◽

Clinical Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Study Selection ◽

The Impact ◽

Detrimental Impact

e15234 Background: Corticosteroids are commonly used for management of cancer-related symptoms or immune-related adverse events (irAEs) in cancer patients treated with immune checkpoint inhibitors (ICIs). However, given the inhibitory effects of corticosteroids on a broad range of immune responses, it is presumed that the use of these agents may affect the clinical outcomes of ICIs. This meta-analysis aims to explore the impact of corticosteroids use on the efficacy of ICIs in cancer patients. Methods: We conducted a search covering electronic databases (MEDLINE, EMBASE, and CENTRAL), conference abstracts (ASCO and ESMO) and reference lists to identify relevant studies. Studies that reported clinical outcomes of patients with corticosteroids administration before and/or after the initiation of ICIs treatment were eligible for evaluation. The primary outcomes included progression-free survival (PFS) and overall survival (OS). The random-effects model was utilized to synthesize the effect sizes of individual studies. Results: The initial literature search identified 1,900 records. After study selection, a total of 15 studies with 14,123 patients were included in the quantitative analysis. Corticosteroids use significantly reduced PFS (HR = 1.84; 95% CI: 1.30–2.61; P = 0.001) and OS (HR = 1.41; 95% CI: 1.18–1.68; P < 0.001) in cancer patients treated with ICIs. In subgroup analysis, corticosteroids use for cancer-related symptoms was associated with a shorter PFS (HR = 1.98; 95% CI: 1.40–2.78; P < 0.001) and OS (HR = 1.88; 95% CI: 1.25–2.83; P = 0.003), but their use for irAEs did not show a detrimental impact on OS (HR = 1.05; 95% CI: 0.77–1.44; P = 0.740). Conclusions: This meta-analysis indicated that corticosteroids use might hinder the efficacy of ICIs in cancer patients. The indications of corticosteroids use should be strictly controlled during the course of immunotherapy.

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Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919861905 ◽

2019 ◽

Vol 11 ◽

pp. 175883591986190 ◽

Cited By ~ 9

Author(s):

Giandomenico Roviello ◽

Silvia Paola Corona ◽

Gabriella Nesi ◽

Enrico Mini

Keyword(s):

Overall Survival ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Pooled Analysis ◽

First Line

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36–0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72–0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57–0.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

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Clinical significance of tumour mutation burden in immunotherapy across multiple cancer types: an individual meta-analysis

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa076 ◽

2020 ◽

Vol 50 (9) ◽

pp. 1023-1031

Author(s):

Zhenyu Yang ◽

Shiyou Wei ◽

Yulan Deng ◽

Zihuai Wang ◽

Lunxu Liu

Keyword(s):

Overall Survival ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Cancer Type ◽

Free Survival ◽

Mutation Burden

Abstract Background Biomarkers for stratifying patients that could benefit from immune checkpoint inhibitors are necessary. Tumour mutation burden has recently become a promising biomarker in cancer, but the associations between tumour mutation burden and outcomes of immune checkpoint inhibitors treatment were not well-documented in present studies. Methods We searched PubMed, Web of Science and EMBASE databases up to 1 October 2019. Studies evaluated the association between tumour mutation burden and clinical outcomes were included. Hazard ratios and odds ratios were applied to estimate the association of tumour mutation burden score with overall survival, progression-free survival and response rate, respectively. The best cut-off value was chosen by best discriminated overall survival using Contal and O’Quigley method. Results Twenty-two studies involving 6171 patients in diverse cancers were included. The individual participant data meta-analysis demonstrated that high tumour mutation burden was associated with better overall survival (HR = 0.57, 95% CI = 0.50–0.64) and progression-free survival (HR = 0.50, 95% CI = 0.40–0.63) and higher response rate. The best cut-off values in each cancer type were 17.7/MB in non-small cell lung cancer, 7.9/MB in bladder cancer, 6.1/MB in melanoma, 12.3/MB in colorectal cancer, 6.9/MB in esophagogastric cancer, 10.5/MB in head and neck cancer. The pooled meta-analysis showed the prognosis value was robust and the sensitivity, specificity and area under the receiver operating characteristic curves in predicting response rates were 0.63, 0.71 and 0.73, respectively. Conclusions The present meta-analysis indicates tumour mutation burden is a promising predictor of immune checkpoint inhibitors therapy but the cut-off value differs in different cancers.

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Efficacy of immune checkpoint inhibitors in cancer patients of different ages: a meta-analysis

Future Oncology ◽

10.2217/fon-2019-0279 ◽

2019 ◽

Vol 15 (31) ◽

pp. 3633-3646 ◽

Cited By ~ 2

Author(s):

Jing Li ◽

Jian Gu

Keyword(s):

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Age Groups ◽

Progression Free Survival ◽

Systematic Evaluation ◽

Free Survival ◽

Older Cancer Patients

Aim: We conducted an up-to-date meta-analysis of randomized controlled trials (RCTs) to compare the immune checkpoint inhibitors (ICIs) in different age groups. Methods: The relevant RCTs in cancer patients receiving ICIs were searched and the systematic evaluation was performed. PubMed, MEDLINE and EMBASE were searched for studies published till January 2019. Results: A total of 27 RCTs included 17,546 patients were available for this meta-analysis. ICIs significantly improved overall survival (OS) and progression-free survival (PFS) in both of the younger (<65 years) and the older cancer patients (≥65 years). No significantly prolonged OS and PFS was observed among patients older than 75 years. Conclusion: ICIs could not significantly improve OS and PFS compared with controls in cancer patients aged over 75 years.

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How to Choose a Survival Period? The Impact of Antibiotic Use on OS or PFS in NSCLC Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Technology in Cancer Research & Treatment ◽

10.1177/15330338211033498 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110334

Author(s):

Hua Chen ◽

Ke-dong Han ◽

Zhi-jiang He ◽

Yi-sheng Huang

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Antibiotic Use ◽

Sensitivity Analyses ◽

Clinical Activity ◽

Nsclc Patients ◽

The Impact

Background: The development of immunotherapy has dramatically changed the treatment of non-small-cell lung cancer. The negative association of antibiotics on the clinical activity of immune checkpoint inhibitors in patients with NSCLC is well known. Methods: PubMed, Embase, and Medline databases were searched until January 11, 2020. We included retrospective studies of ICIs (e.g., PD-1, PD-L1, and CTLA-4). The clinical outcomes were progression-free survival (PFS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated, and subgroup and sensitivity analyses were performed. Results: Our results indicated that the use of antibiotics reduced the survival of NSCLC patients treated with ICIs. The pooled HRs of PFS and OS were HR = 1.41 (95% CI = 1.23-1.61; P < 0.001) and HR = 2.16 (95% CI = 1.79-2.60; P < 0.001). We divided the studies into 5 subgroups according to antibiotic exposure time. Subgroup analysis showed that the patients that were administered antibiotics [−60 days; 0 days] or [−30 days; 0 days] before the initiation of ICIs treatment had a poorer OS rate, whereas those patients that were administered antibiotics [0 days; 30 days] after the initiation of ICIs treatment had a poorer PFS rate. In summary, ATB treatment in patients [−60 days; +30 days] near the initiation of ICIs treatment significantly reduced the survival in NSCLC patients. Conclusion: Our results indicated that ATB use is negatively associated with survival in NSCLC patients treated with ICIs immunotherapy. Similar studies involving a larger sample of cases are still being published. This meta-analysis identified that the timing of ATB treatment in NSCLC patients receiving ICIs immunotherapy has different effects on the OS and PFS of these patients. ATB treatment prior to the initiation of ICIs treatment affects OS, whereas ATB treatment after the initiation of ICIs treatment affects PFS.

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