scholarly journals The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

2020 ◽  
Author(s):  
Lihu Gu ◽  
Shengnan Li ◽  
Nannan Du ◽  
Qigu Yao ◽  
Xiaojun Fu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Cochrane Library ◽  
Effect Estimate ◽  
Grade 3 ◽  
Combined Immunotherapy

Abstract Background: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab-ipilimumab combination therapy in cancer treatment. Methods: We examined data from PubMed, Web of science, EBSCO and Cochrane library. Eleven articles fulfilled our criteria, which we divided into 3 groups; nivolumab and ipilimumab versus ipilimumab, nivolumab and ipilimumab versus ipilimumab and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR) and TRAEs in any grade and grade 3 or higher. Results: Compared with ipilimumab alone, the combined immunotherapy had better CR (RR: 4.89, p <0.001), PR (RR: 2.75, p <0.001), and ORR (RR: 3.31, p <0.001). The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p <0.001) and PR (RR: 1.50, p <0.001) than nivolumab alone. Finally, N1I3 showed better PR (RR: 1.35, p =0.006) and ORR (RR: 1.21, p =0.03) than N3I1. The incidence of any TRAEs was similar between the both groups (RR: 1.05, p =0.06). However, the incidence of serious adverse events (grade 3 or higher) were lower in group N3I1 than group N1I3 (RR: 1.51, p <0.001). Conclusion: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of ipilimumab or nivolumab monotherapy. In the combination group, N1I3 combination was more effective than N3I1. Although the side effects were slightly increased in group N1I3, the overall safety was acceptable.

scholarly journals Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3629
Author(s):  
Hsiao-Ling Chen ◽  
Yu-Kang Tu ◽  
Hsiu-Mei Chang ◽  
Tai-Huang Lee ◽  
Kuan-Li Wu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Small Cell ◽  
Randomized Controlled ◽  
Extensive Stage ◽  
Grade 3

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

scholarly journals Comparative risk of serious and fatal treatment-related adverse events caused by 19 immune checkpoint inhibitors used in cancer treatment: a network meta-analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592094092 ◽  
Author(s):  
Tingting Liu ◽  
Bo Jin ◽  
Jun Chen ◽  
Hui Wang ◽  
Shuiyu Lin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Combinatorial Therapy ◽  
Grade 5 ◽  
Comparative Risk ◽  
Grade 3

Background: This network meta-analysis assessed the comparative risk of grade 3–5 and grade 5 treatment-related adverse events (TRAEs) for immune checkpoint inhibitors (ICIs), either alone or in combination with other modalities, for cancer treatment. Methods: PubMed, Embase, Cochrane Library, Web of Science, and recent predominant oncology congresses were searched for relevant phase II and phase III randomized controlled trials (RCTs). As outcomes, grade 3–5, and grade 5 TRAE outcomes were reported as odds ratios and 95% confidence intervals. Results: In 67 RCTs involving 36,422 patients and 19 ICIs, the incidence of grade 3–5 and grade 5 TRAEs was 17.9% and 0.8% with ICI monotherapy and 46.3% and 1.4%, respectively, with combinatorial therapy. Pneumonitis was the most common cause of grade 5 TRAEs following either monotherapy (16.3%) or combinatorial therapy (11.4%). Regarding grade 3–5 TRAEs, atezolizumab + chemotherapy (CT) and antiangiogenic therapy (AT) (atezolizumab + CAT), pembrolizumab + CT, ipilimumab + CT, and atezolizumab + CT were more toxic than any ICI monotherapy, pembrolizumab or nivolumab + radiotherapy (RT), and ICIs dual therapy (durvalumab + tremelimumab and nivolumab + ipilimumab). Tremelimumab, ipilimumab, durvalumab, and pembrolizumab were, however, associated with higher grade 5 TRAEs than combinatorial treatments. Atezolizumab + CAT was the most toxic and nivolumab + RT was the least toxic of combinatorial treatments; among monotherapies, tremelimumab and avelumab were the most and least toxic, respectively. The toxicity ranking changed with type of grade 3–5 TRAEs. Conclusions: Compared with combinatorial therapy, ICI monotherapy caused lower grade 3–5 TRAEs, but some monotherapies resulted in a higher incidence of fatal TRAEs. Atezolizumab + CAT and nivolumab + RT were the most and least toxic of combinatorial treatments, respectively, and tremelimumab and avelumab were the most and least toxic of the monotherapies, respectively.

The safety and efficacy of immune-checkpoint inhibitors in patients with cancer and pre-existing autoimmune diseases

Immunotherapy ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 527-539
Author(s):  
Chunlan Wu ◽  
Li Zhong ◽  
Qing Wu ◽  
Shaowei Lin ◽  
Xianhe Xie
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Cochrane Library ◽  
Antitumor Effects ◽  
Safety And Efficacy ◽  
Patients With Cancer ◽  
Early Use ◽  
Grade 3

Objective: This study aims at investigating the safety and efficacy of immune-checkpoint inhibitors (ICIs) in patients with cancer and pre-existing autoimmune disease (AID). Materials & methods: PubMed, Embase and Cochrane Library were searched for relevant studies. The primary end points of the study were immunotoxicity and cancer response. Results: At the early use of ICIs, compared with those with active AID, grade 3–4 AID flare occurred more frequently in patients with inactive AID after treatment with ICIs; and the incidence of grade 3–4 immunotoxic effects was significantly lower in patients undergoing immunosuppressive therapy than those without corresponding treatment. In addition, patients with worsening AID generally obtained a better objective response than those without a flare. Conclusion: This study demonstrates that the toxic effects induced by immunotherapy are generally manageable in patients with cancer and pre-existing AID, some of whom even achieve satisfactory antitumor effects in clinical practice.

Treatment-related adverse events of combination immune checkpoint inhibitors: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15060-e15060
Author(s):  
Robin Park ◽  
Laércio Lopes da Silva ◽  
Ivy Riano ◽  
Cagney Cristancho ◽  
Anwaar Saeed
Keyword(s):  
Adverse Event ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Related Adverse Event ◽  
Adverse Event Data ◽  
Cancer Types ◽  
Grade 3

e15060 Background: Despite increasing clinical experience with immune checkpoint inhibitors and the recent publication of clinical practice guidelines for managing treatment-related adverse events, precise and nuanced checkpoint inhibitor data in the setting of combination therapy is lacking. Herein we have conducted a systematic review and meta-analysis of treatment-related adverse event data from clinical trials evaluating combination immune checkpoint inhibitors. Methods: Studies published in PubMed, Embase, and Cochrane Database from conception to September 28, 2019 were included in the meta-analysis. Studies were eligible for inclusion if combination immune checkpoint inhibitor therapy was evaluated in advanced unresectable cancer and treatment-related adverse event data were available. For comparison of severity of adverse events in combination versus monotherapy, only the studies containing monotherapy arms as a control population were included, while all were included for calculation of pooled incidence of selected adverse events. Pooled risk ratio (RR) was used for the comparison of combination versus monotherapy and the logit transformed proportion for calculation of pooled incidence. Between-study risk of bias was evaluated using the Begg's funnel plot and Egger's regression test. Subgroup analysis was conducted by combination regimen, cancer type, and dosing regimen. Results: A total of 18 studies comprising 2767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment type (PD-1+CTLA-4 and PD-L1+CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1 and D20T1). Incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945] and grade 3 or higher events/all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusions: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.

A comprehensive meta-analysis of endocrine immune-related adverse events of immune checkpoint inhibitors and outcomes in head and neck cancer and lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14096-e14096 ◽  
Author(s):  
Cristiane Jeyce Gomes-Lima ◽  
John Kwagyan ◽  
Fred King ◽  
Stephen J Fernandez ◽  
Kenneth D Burman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Head And Neck Cancer ◽  
Adverse Events ◽  
Neck Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Grade 3

e14096 Background: Immune checkpoint inhibitors (ICPi) have emerged as an effective treatment for a variety of cancers. However, important immune-related adverse events (irAEs) can occur. The aim of this study was to determine the prevalence of endocrine irAEs in patients with head and neck cancer and lung cancer that have used a ICPi and outcomes. Methods: A systematic literature review was performed within PubMed and EMBASE databases. Search terms included “durvalumab”, “atezolizumab”, “nivolumab”, “pembrolizumab”, “ipilimumab”, “head & neck cancer”, “lung cancer”. Studies published before September 2018 were included. The search was limited to randomized controlled trials (RCTs) phase III written in English. Data were extracted about patient characteristics, interventions, overall survival (OS), progression free survival (PFS), and endocrine irAEs. A summary hazard ratio (HR) and 95% confidence interval were calculated using the software Comprehensive Meta-Analysis and a scatter plot was generated. Results: Twelve RCTs comprising 7060 patients were reviewed; 3815 used an ICPi (treatment arm). The mean follow-up time of 12.2 months ± 7.1 SD. The survival rate of the treatment arm was enhanced (HR, 0.75; 95% CI, 0.70-0.80), compared to the alternate arm. Similarly, the PFS of the treatment arm was improved (HR, 0.77; 95% CI, 0.72-0.81) but with a higher incidence of endocrine irAEs. The most common endocrine irAE reported was hypothyroidism;193 patients in the treatment arm vs. 29 in the alternate arm (p < 0.001); grade 3/4 AE was observed in 10 patients vs. 1 patient, respectively. Other endocrine irAEs were reported in 168 patients in the treatment arm vs. 26 patients in the alternate arm (p < 0.001); grade 3/4 AE was observed in 28 patients vs. 3 patients, respectively. A significant positive correlation between endocrine irAEs and OS was observed (p = 0.019). Conclusions: ICPi are a powerful tool in the treatment of cancer. The prevalence of endocrine irAEs in this meta-analysis was 9%. There is evidence of improved overall survival in patients who developed endocrine irAEs. Further studies are needed to correlate the development of irAEs and OS advantage.

Effect of immunotherapy on survival outcomes in prostate cancer: Systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17030-e17030
Author(s):  
Vinod solipuram ◽  
Kishor Pokharel ◽  
Bhanu Prasad Venkatesulu ◽  
Harideep Samanapally
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Overall Survival ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Standard Treatment ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Grade 3

e17030 Background: Prostate cancer is one of the leading cancers in men with an estimated 191,930 new cases in 2020 in the USA alone. Treatment options for metastatic castration resistant prostate cancer (mCRPC) have evolved in recent years. Immunotherapy involving vaccines like sipuleucel-T, PROSTVAC and immune checkpoint inhibitors have been evaluated in these patients. We present a systematic review and meta-analysis of the randomized controlled trials (RCTs) testing the effect of immunotherapy in mCRPC. Methods: A systematic search was performed using PubMed, Embase and the Cochrane library without language limitations from inception to January 3, 2021. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), prostate specific antigen (PSA) reduction ≥ 50% and incidence of grade 3-4 adverse events. The analysis of OS, PFS was done using random effects hazard ratio (HR) by generic inverse variance method and analysis of PSA reduction ≥ 50% and grade 3-4 adverse events was done using random effects risk ratio (RR) by the Mantel-Haenszel method. Results: 12 RCTs comprising 4109 patients were included in the analysis. There was a statistically significant improvement in OS (HR 0.89; 95% CI (0.81, 0.97)) and PFS (HR 0.83; 95% CI (0.76, 0.92)) in the immunotherapy arm compared to placebo or standard treatment arms with moderate quality of evidence. Patients in the immunotherapy group had significant reduction in PSA ≥ 50% (RR 1.71; 95% CI (1.09, 2.68)) but also had statistically significant increased risk of grade 3-4 adverse events (RR (1.25; 95% CI (1.02, 1.54)) when compared to placebo and the standard treatment group. Subgroup analysis showed that the use of vaccine therapy in prostate cancer leads to significant improvement in OS (HR 0.83; 95% CI (0.74, 0.93)) and PFS (HR 0.80; 95% CI (0.67, 0.95)) compared to placebo and standard treatment. The use of immune checkpoint inhibitors was not associated with statistically significant improvement in OS (HR 0.98; 95% CI (0.88, 1.09)) but is associated with improvement in PFS (HR 0.87; 95%CI (0.81, 0.94)). Conclusions: This meta-analysis showed that immunotherapy led to significant improvement in OS, PFS and PSA reduction of ≥ 50%. However, there is an increased incidence of grade 3-4 adverse events with the use of immunotherapy when compared to other standard therapies and placebo. The improvement in overall survival is limited to the use of vaccine therapy and not to immune checkpoint inhibitors. Careful use of selective forms of immunotherapy in mCRPC can lead to greater improvement in survival.

Outcomes following immunotherapy re-challenge after immune-related adverse event: systematic review and meta-analysis

Immunotherapy ◽  
2020 ◽  
Vol 12 (16) ◽  
pp. 1183-1193
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Odds Ratio ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Cochrane Database ◽  
Grade 3

Background: Given the inconclusive evidence behind the safety and efficacy of immune checkpoint inhibitors re-challenge, herein, we have conducted a systematic review and meta-analysis to synthesize available data. Results/methodology: PubMed, Embase, Cochrane Database, and ASCO and ESMO were searched for studies published from conception to March 2020. Pooled incidence of recurrent immune-related adverse events (irAEs), objective response rates, and odds ratios for irAEs at initial versus re-treatment were calculated. Overall, 437 patients (ten studies) were included. Incidence of any grade, grade 3/4, and steroid-requiring recurrent irAEs were 47%, 13.2%, and 26% respectively. Objective response rate in previous non-responders was 12.5% (5.8–24.8%). Odds ratio for severe irAEs was 0.28 (0.11–0.72) and steroid-requiring irAEs 0.19 (0.06–0.56). Discussion/conclusion: This analysis suggests that immune checkpoint inhibitors re-challenge is safe and potentially efficacious.

scholarly journals Immune-Related Adverse Events Predict the Efficacy of Immune Checkpoint Inhibitors in Lung Cancer Patients: A Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Donghui Wang ◽  
Cen Chen ◽  
Yanli Gu ◽  
Wanjun Lu ◽  
Ping Zhan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Lung Cancer Patients

BackgroundImmune-related adverse events (irAEs) have been reported to be associated with the efficacy of immunotherapy. Herein, we conducted a meta-analysis to demonstrate that irAEs could predict the efficacy of immune checkpoint inhibitors (ICIs) in lung cancer patients.MethodsLiterature on the correlation between irAEs and the efficacy of immunotherapy in lung cancer patients were searched to collect the data on objective response rate (ORR), overall survival (OS), or progression-free survival (PFS) of the patients. These data were incorporated into the meta-analysis.ResultsA total of 34 records encompassing 8,115 patients were examined in this study. The irAEs occurrence was significantly associated with higher ORR {risk ratio (RR): 2.43, 95% confidence interval (CI) [2.06–2.88], p &lt; 0.00001} and improved OS {hazard ratio (HR): 0.51, 95% CI [0.43–0.61], p &lt; 0.00001}, and PFS (HR: 0.50, 95% CI [0.44–0.57], p &lt; 0.00001) in lung cancer patients undergoing ICIs. Subgroup analysis revealed that OS was significantly longer in patients who developed dermatological (OS: HR: 0.53, 95%CI [0.42–0.65], p &lt; 0.00001), endocrine (OS: HR: 0.55, 95%CI [0.45–0.67], p &lt; 0.00001), and gastrointestinal irAEs (OS: HR: 0.58, 95%CI [0.42–0.80], p = 0.0009) than in those who did not. However, hepatobiliary, pulmonary, and high-grade (≥3) irAEs were not correlated with increased OS and PFS.ConclusionThe occurrence of irAEs in lung cancer patients, particularly dermatological, endocrine, and gastrointestinal irAEs, is a predictor of enhanced ICIs efficacy.

scholarly journals Comparative Risk of Renal Adverse Events in Patients Receiving Immune Checkpoint Inhibitors: A Bayesian Network Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Kang Liu ◽  
Zhongke Qin ◽  
Xueqiang Xu ◽  
Ting Li ◽  
Yifei Ge ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Cancer Therapy ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Increased Risk ◽  
The Difference ◽  
Grade 3

BackgroundImmune checkpoint inhibitors (ICIs) have brought a paradigm shift to cancer treatment. However, little is known about the risk of renal adverse events (RAEs) of ICI-based regimens, especially ICI combination therapy.MethodsWe carried out a network meta-analysis of randomized controlled trials (RCTs) to compare the risk of RAEs between ICI-based regimens and traditional cancer therapy, including chemotherapy and targeted therapy. Subgroup analysis was conducted based on tumor types.ResultsNinety-five eligible RCTs involving 40,552 participants were included. The overall incidence of RAEs, grade 3–5 RAEs, acute kidney injury (AKI), and grade 3–5 AKI was 4.3%, 1.2%, 1.3%, and 0.8%, respectively. Both ICI-based treatment regimens and traditional cancer therapy showed significantly higher risk of RAEs and AKI than the placebo. Among ICI monotherapy, anti-PD-1 (RR: 0.51, 95%CI: 0.29–0.91) was significantly safer than anti-CTLA-4 in terms of RAEs. Anti-CTLA-4 showed significantly higher toxicity than anti-PD-1 (RR: 0.33, 95%CI: 0.14-0.77), anti-PD-L1 (RR: 0.38, 95%CI:0.16-0.91), and anti-PD-1 plus anti-CTLA-4 (RR: 0.32, 95%CI: 0.12-0.87) in terms of grade 3-5 RAEs. The difference was not significant between ICI monotherapy and traditional cancer therapy, except that targeted therapy seemed the least toxic therapy in terms of the incidence of AKI. Anti-CTLA-4 plus anti-PD-1 were associated with higher risk of RAEs than anti-PD-1 (RR: 1.61, 95%CI: 1.02–2.56). The difference was not significant between other dual ICI regimens and ICI monotherapy in terms of RAEs and AKI. ICI plus chemotherapy showed increased risk of both RAEs and AKI compared with ICI monotherapy, chemotherapy, and targeted therapy. The overall results remained robust in the meta-regression and sensitivity analyses.ConclusionsAmong ICI monotherapy, anti-CTLA-4 appeared to be associated with increased toxicity, especially in terms of grade 3–5 RAEs. Anti-CTLA-4 plus anti-PD-1 were associated with higher risk of RAEs than anti-PD-1. However, the difference was not significant between other dual ICI regimens and ICI monotherapy in terms of RAEs and AKI. ICIs plus chemotherapy seemed to be the most toxic treatment regimen in terms of RAEs, AKI, and grade 3–5 AKI.Systematic Review RegistrationPROSPERO, identifier CRD42020197039.

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