Dataset Information

Risk of Pneumonitis Associated With Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis.

ABSTRACT:

Background

Immune checkpoint inhibitors (ICIs) have dramatically altered the treatment landscape for patients with melanoma. However, their use also generates unique immune-related adverse effects (irAEs). We performed a systematic review and network meta-analysis to compare the risk of pneumonitis associated with ICIs for patients with advanced or metastatic melanoma.

Methods

Phase II/III randomized clinical trials (RCTs) with ICIs were identified through comprehensive searches of multiple databases. An NMA was conducted to compare the risk of pneumonitis associated with ICIs and all-grade (grade 1-5) and high-grade (grade 3-5) immune-related pneumonitis (IRP) were estimated by odds ratios (ORs).

Results

A total of 10 randomized clinical trials involving 5,335 patients were enrolled in this study. Conventional chemotherapy was associated with a lower risk of grade 1-5 IRP compared with ICIs monotherapy (OR, 0.14, 95% CI, 0.03 to 0.73) and dual ICIs combination (OR, 0.03, 95% CI, 0.00 to 0.19). In addition, dual ICIs combination showed a noticeably higher risk than ICI monotherapy (OR, 4.45, 95% CI, 2.14 to 9.25) of grade 1-5 IRP. No significant difference in grade 1-5 IRP was observed between cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors. As to grade 3-5 IRP, no statistically significant difference was found among different ICIs-based regimens.

Conclusion

These findings revealed that ICIs could increase the risk of all-grade pneumonitis for patients with advanced melanoma, compared with conventional chemotherapy. Dual ICIs combination could further increase the risk of all-grade pneumonitis than ICIs monotherapy. There was no significant difference in the risk of pneumonia between CTLA-4 and PD-1 inhibitors.

SUBMITTER: Sun YM

PROVIDER: S-EPMC8568299 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Risk of Pneumonitis Associated With Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis.

Sun You-Meng YM Li Wei W Chen Zhi-Yu ZY Wang Ying Y

Frontiers in oncology 20211021

<h4>Background</h4>Immune checkpoint inhibitors (ICIs) have dramatically altered the treatment landscape for patients with melanoma. However, their use also generates unique immune-related adverse effects (irAEs). We performed a systematic review and network meta-analysis to compare the risk of pneumonitis associated with ICIs for patients with advanced or metastatic melanoma.<h4>Methods</h4>Phase II/III randomized clinical trials (RCTs) with ICIs were identified through comprehensive searches o ...[more]

PMID: 34745932

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Project description:Background: We performed a systematic review and meta-analysis to evaluate the risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors (ICIs) for solid tumors. Methods: The following keywords were used in searching the Embase and PubMed database: pneumonitis, pneumonia, and immune checkpoint inhibitors. The data was analyzed by using the R software and Metafor package. Results: Among 3,436 studies, 23 randomized clinical trials (RCTs) met our selection criteria which included data from 12,876 patients. Compared with chemotherapy, PD-1 inhibitors showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR, 5.17, 95% CI: 2.82-9.47, p < 0.001; RR, 4.14, 95% CI: 1.82-9.42, p < 0.001), but not in pneumonia. PD-L1 inhibitors showed significant increase in grade 1-5 pneumonitis and pneumonia (RR, 3.25, 95% CI: 1.61-6.57, p < 0.001; RR, 2.11, 95% CI: 1.20-3.70, p < 0.001). There was no significant difference in any grade pneumonitis and pneumonia in cytotoxic T lymphocyte-associated protein 4 (CTLA4) inhibitors subgroup. Programmed cell death protein 1 (PD-1) inhibitor (nivolumab and pembrolizumab) both showed significant increase in grade 1-5 pneumonitis, and pembrolizumab specially tended to increase grade 3-5 pneumonitis. (RR, 5.64 95% CI: 1.94-16.38, p < 0.001). Compared with PD-1 inhibitor (nivolumab) or CTLA-4 inhibitor (ipilimumab) monotherapy, PD-1 inhibitor, and CTLA-4 inhibitor (nivolumab plus ipilimumab) combination therapies showed significant increase in grade 1-5 and grade 3-5 pneumonitis (RR 3.47, 95%CI:1.76-6.83, p < 0.001; RR 3.48, 95%CI: 1.10-11.02, p < 0.001). Conclusions: PD-1/PD-L1 inhibitors treatment could increase the risk of all-grade pneumonitis. CTLA4 inhibitor ipilimumab treatment alone could not increase the risk of pneumonitis but could augment the risk of pneumonitis in PD-1/PD-L1 inhibitor treated patients. There was no significant increase in the risk of pneumonia after either PD-1/PDL-1inhibitor or CTLA4 inhibitor treatment alone or in combination.

Project description:ImportanceSince 2011, immune checkpoint inhibitors (ICIs) have been effective treatment options for advanced melanoma. Little is known about how risks of immune-related adverse events (irAEs) vary by ICIs.ObjectiveTo compare the risk of irAEs across different treatment regimens for advanced melanoma using network meta-analysis.Data sourcesPubMed/MEDLINE, Embase, Web of Science, and Scopus were searched for all randomized clinical trial (RCT) articles published from January 1, 2010, through June 30, 2019.Study selectionStudies included phases 2 and 3 RCTs in the treatment of advanced melanoma that compared ICIs (ipilimumab, nivolumab, and pembrolizumab) with chemotherapy drugs (eg, dacarbazine, carboplatin, and paclitaxel) or different ICI regimens.Data extraction and synthesisDifferent treatment regimens were compared using bayesian network meta-analysis with Markov chain Monte Carlo simulation with noninformative prior distribution and random-effects generalized linear models.Main outcomes and measuresPrimary outcomes were the cumulative incidence of any irAEs (regardless of severity) and severe irAEs (grades 3-5). Based on the pooled odds ratios (ORs) and 95% credible intervals (95% CrI), the probability of being associated with the lowest irAE risks was estimated for each treatment regimen.ResultsNine RCTs with 8 different treatment regimens for advanced melanoma and involving a total of 5051 patients were included. Overall, the 3 ICI treatment regimens associated with the lowest risk of any or severe irAEs were pembrolizumab, 2 mg/kg, every 3 weeks; nivolumab, 3 mg/kg, every 2 weeks; and pembrolizumab, 10 mg/kg, every 3 weeks. Compared with ipilimumab, 10 mg/kg, every 3 weeks, only nivolumab, 3 mg/kg, every 2 weeks, was associated with a decreased risk for any irAEs (OR, 0.34; 95% CrI, 0.13-0.94). A decreased risk for severe irAEs was observed for ipilimumab, 3 mg/kg, every 3 weeks (OR,?0.35; 95% CrI,?0.14-0.74); pembrolizumab, 10 mg/kg, every 2 weeks (OR,?0.22; 95% CrI,?0.05-0.95) and 10 mg/kg every 3 weeks (OR,?0.20; 95% CrI,?0.06-0.68); and nivolumab, 3 mg/kg, every 2 weeks (OR,?0.20; 95% CrI,?0.07-0.48) compared with ipilimumab, 10 mg/kg, every 3 weeks. An increased risk for severe irAEs was associated with nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks compared with other ICI regimens (ORs ranging from?4.09 [95% CrI, 1.73-10.99] to 7.40 [95% CrI, 1.12-49.29]) except ipilimumab, 10 mg/kg, every 3 weeks.Conclusions and relevanceThese findings suggest that for patients with advanced melanoma at high risk of irAEs, pembrolizumab, 2 mg/kg, every 3 weeks, nivolumab, 3 mg/kg, every 2 weeks, and pembrolizumab, 10 mg/kg, every 3 weeks may be the preferred treatment regimens (with respect to irAE risks) among the ICI regimens reported, whereas ipilimumab, 10 mg/kg, every 3 weeks alone and nivolumab, 1 mg/kg, every 3 weeks combined with ipilimumab, 3 mg/kg, every 3 weeks should be used with caution. A network analysis may be valuable for clinical decision-making when evidence from head-to-head comparisons is lacking.

Project description:Rates of malignant melanoma are continuing to increase, and until recently effective treatments were lacking. However, since 2011 three immunotherapeutic agents, known as checkpoint inhibitors, have been approved. This review aims to establish whether these three drugs - ipilimumab, nivolumab, and pembrolizumab - offer greater efficacy and tolerability compared to control interventions (placebo, immunotherapy, or chemotherapy) in patients with stage III or IV unresectable cutaneous melanoma.A search on four major medical and scientific databases yielded 7,553 records, of which seven met the inclusion criteria, with a total study population of 3,628. Only prospective Phase II or III randomized controlled trials on checkpoint inhibitors for patients with unresectable cutaneous melanoma that reported data on survival (overall or progression-free), tumor response, or adverse events were included. Three meta-analyses were carried out.The hazard ratio for progression or death was 0.54 (95% confidence interval [CI]: 0.44-0.67), and the odds ratio for best overall response rate was 4.48 (95% CI: 2.77-7.24), both in favor of checkpoint inhibitors. However, control treatments were associated with an insignificantly lower rate of discontinuation of treatment due to adverse effects or treatment-related adverse events (odds ratio =1.63 [95% CI: 0.55-4.88]).This study finds that checkpoint inhibitors are more effective than control interventions, both in terms of survival and tumor response, and yet no less tolerable. PD1 therapies (nivolumab and pembrolizumab) appear to offer greater efficacy than CTLA4 therapy (ipilimumab). The combination of nivolumab and ipilimumab was, however, the most effective, but significantly less tolerable than monotherapy. The lack of published clinical data does, however, limit this study. Further research is needed in two areas in particular: 1) to determine the optimal use of checkpoint inhibitors, specifically in terms of combination therapy, and 2) to identify reliable biomarkers to predictive responders and guide treatment assignment.

Project description:IntroductionAcral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM.MethodsThis systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles.ResultsThis systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies.ConclusionsICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.

Project description:Background: Multiple immune checkpoint inhibitors (ICIs) and targeted therapies have been widely used as adjuvant treatments for high-risk resected melanoma, with unclear comparative efficacy and safety. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 6 June 2023. We included RCTs that assess adjuvant ICIs or targeted therapies in high-risk resected melanoma. Frequentist random-effect network meta-analyses (NMA) were performed. The primary outcome was recurrence-free survival (RFS). Results: Eleven trials including 10,712 patients and comparing 10 treatments (nivolumab [Nivo], ipilimumab 3 mg/kg [Ipi3], Ipi10, pembrolizumab [Pemb], vemurafenib [Vemu], bevacizumab [Beva], Nivo + Ipi1, Nivo + Ipi3, dabrafenib plus trametinib [Dab + Tram], and placebo/observation [Pla/Obs]) were included. NMA showed that all treatments showed RFS benefit over placebo/observation except Ipi3 (hazard ratio [HR], 0.78; 95% CI, 0.58-1.05). Combination therapy of Nivo + Ipi3 was the most effective treatment, which significantly improved RFS compared with other treatments. NMA also showed that all treatments were associated with an increased risk of grade 3-5 adverse events over placebo/observation except Nivo (HR, 1.25; 95% CI, 0.87-1.80). NMA suggested that Nivo and Pemb were the two safest treatments except for placebo/observation. Although three combination therapies ranked as the top three in terms of RFS, they did not show significant overall survival benefits compared to monotherapies including Pemb, Nivo, Ipi3, and Ipi10. Conclusion: In this NMA, adjuvant Nivo and Pemb are the preferred options in patients with resected melanoma considering the benefits and harms. Combination therapy of Nivo + Ipi3 may be a promising strategy, but more evidence from phase 3 trials is needed. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=438667, PROSPERO (CRD42023438667).

Project description:ObjectiveTo provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.DesignSystematic review and network meta-analysis.Data sourcesElectronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.Review methodsOnly head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.Results36 head-to-head phase II and III randomised trials (n=15?370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.ConclusionsCompared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.Systematic review registrationPROSPERO CRD42017082553.

Dataset Information

Risk of Pneumonitis Associated With Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis.

Background

Methods

Results

Conclusion

Publications

Risk of Pneumonitis Associated With Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis.

Similar Datasets

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