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Fatal Adverse Events Associated With Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

ABSTRACT: Background: Immune checkpoint inhibitors (ICIs) have previously been reported to have a promising potential in terms of the improvement of outcomes in non-small cell lung cancer (NSCLC). Fatal adverse events (FAEs) of ICIs are relatively uncommon, and the incidence and risk in NSCLC remain unclear. In the present study, we conducted a systematic review and meta-analysis to evaluate the risk of FAEs in NSCLC patients administered with ICIs. Methods: Potentially relevant studies were identified in PubMed, EMBASE, and Cochrane library database from inception to September 16, 2020. The systematic review and meta-analysis included randomized controlled trials that reported treatment-related FAEs in NSCLC. The pooled incidence and risk ratios (RRs) were calculated to evaluate prospective risk. Results: Twenty clinical trials that included a total of 13,483 patients were selected for the meta-analysis. The overall incidence of FAEs was 0.65% [95% confidence interval (CI) = 0.31-1.07, I ² = 50.2%] in ICI monotherapy, 1.17% (95% CI = 0.74-1.69, I ² = 56.3%) in chemotherapy, and 2.01% (95% CI = 1.42-2.69, I ² = 5.9%) in the combination therapy (ICI and chemotherapy). ICI monotherapy was associated with lower incidence of FAEs caused by blood system disorders (RR = 0.23, 95% CI = 0.07-0.73, P = 0.013, I ² = 0%) and infectious diseases (RR = 0.29, 95% CI = 0.13-0.63, P = 0.002, I ² = 0%). The incidence of pneumonitis significantly increased in immunotherapy (RR = 5.72, 95% CI = 1.14-28.80, P = 0.03, I ² = 0%). Conclusions: The results of the present study demonstrate that ICI monotherapy decreases the risk of FAEs, whereas the combined regimens with chemotherapy have the opposite tendency as compared to conventional chemotherapy. While the patients who received chemotherapy suffered the risks of death mainly from myelosuppression and infection, those who received immunotherapy were mainly threatened by immune-related pneumonitis.

SUBMITTER: Yu X

PROVIDER: S-EPMC7917063 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Fatal Adverse Events Associated With Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Yu Xiaolin X Zhang Xiaomei X Yao Ting T Zhang Ye Y Zhang Yanxia Y

Frontiers in medicine 20210215

<b>Background:</b> Immune checkpoint inhibitors (ICIs) have previously been reported to have a promising potential in terms of the improvement of outcomes in non-small cell lung cancer (NSCLC). Fatal adverse events (FAEs) of ICIs are relatively uncommon, and the incidence and risk in NSCLC remain unclear. In the present study, we conducted a systematic review and meta-analysis to evaluate the risk of FAEs in NSCLC patients administered with ICIs. <b>Methods:</b> Potentially relevant studies were ...[more]

PMID: 33659263

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Project description:Objective: This network meta-analysis will provide a complete toxicity profile, toxicity profile, and safety ranking of immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC). Methods: We found 12 phase II or III randomized clinical trials (RCTs) including 8,453 patients with NSCLC by searching Pubmed, Embase, and ClinicalTrials.gov. Risk ratios (RRs) and 95% confidence interval (CI) were used to compare the rate of immune-related adverse events (irAEs) for different ICIs-based treatments using pairwise and network meta-analysis with random effects. Results: For dermatologic irAEs, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab (97.4%), pembrolizumab (80.1%), nivolumab (67.1%), pembrolizumab + platinum (43.3%), atezolizumab + platinum (39.9%), durvalumab (17.5%), platinum-based chemotherapy (4.7%). For colitis, the corresponding ranking of incidences of the six groups from high to low was: atezolizumab + platinum (77.1%), nivolumab (67.3%), pembrolizumab (60.5%), durvalumab (45.2%), pembrolizumab + platinum (41.4%), platinum-based chemotherapy (8.5%). For endocrine irAEs, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab (79.1%), durvalumab (69.1%), pembrolizumab (61.9%), atezolizumab + platinum (60.4%),nivolumab (45.7%), pembrolizumab + platinum (33.5%), platinum-based chemotherapy (0.3%). For pneumonitis, the corresponding ranking of incidences of the seven groups from high to low was: pembrolizumab (99.3%), pembrolizumab + platinum (65.1%), durvalumab (62.2%), atezolizumab + platinum (56%), nivolumab (35.9%), platinum-based chemotherapy (18.1%),atezolizumab (13.3%). For hepatitis, the corresponding ranking of incidences of the six groups from high to low was: pembrolizumab (71.2%), pembrolizumab + platinum (64.3%), durvalumab (56.4%), atezolizumab + platinum (53.8%), nivolumab (44.5%), platinum-based chemotherapy (9.8%). Conlusion: In addition to platinum-based chemotherapy, durvalumab for dermatologic and liver irAEs, pembrolizumab for gastrointestinal irAEs, pembrolizumab + platinum for endocrine irAEs, and atezolizumab for pneumonitis may be associated with lower rates of irAEs than other immune-based regimens. Nivolumab + ipilimumab for dermatologic and endocrine irAEs, atezolizumab + platinum for colitis, and pembrolizumab for pneumonitis and hepatitis may be associated with higher rates of irAEs.

Project description:Background: Immune checkpoint blockade has revolutionized the treatment of multiple malignancies. Currently, however, the effect is not universal, with objective response rates (ORR) of about 15-25%, and even lower for some cancers. Abnormal vasculature is a hallmark of most solid tumors and plays a role in immune evasion. Growing body of evidence suggests that vascular normalization and immune reprogramming could operate synergistic effect, resulting in an enhanced therapeutic efficacy. However, the benefit of antitumor efficacy must be weighed against the risk of added toxicity. In this systematic review, we summarize severe toxicity observed in such a kind of combination regimen. Methods: PubMed and Embase were searched for English references published up to May 31, 2019, with MeSH and keywords search terms of immune checkpoint inhibitors (ICIs) and antiangiogenic agents approved for using in solid tumors. Studies performing concomitant use of ICIs and antiangiogenic agents, and also reporting severe treatment-related adverse events (trAEs) (?grade 3), were included for further analysis. Results: A total of 32 studies including a total of 2,324 participants were analyzed. Limited available data suggests that both antiangiogenic monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) show potential risk of increasing treatment-related toxicity when combined with ICIs. Overall, the total incidence of severe adverse events (AEs) associated with ICIs plus mAbs (44.5%) is lower than that of ICIs plus TKIs (60.1%). However, the trAEs observed in combination therapy are mostly consistent with the known safety profiles of corresponding monotherapy, and they seem to be largely related to antiangiogenic agents, rather than a true immune-related adverse event (irAE) predominantly due to ICIs. The majority of trAEs are intervened by holding ICI treatment and adding corticosteroids, as well as reducing dose or adjusting administration frequency of the antiangiogenic drugs. Conclusions: Concurrent use of ICIs and antiangiogenic agents shows potential treatment-related toxicity. Further research is required to compare the efficacy and safety of the combination regimen and corresponding monotherapy and identify predictive biomarkers, as well as explore dose, duration, and sequencing schedules of drugs.

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:ImportanceImmune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.ObjectiveTo determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.Design, setting, and participantsWe retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally.ExposuresAnti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab).Main outcomes and measuresTiming, spectrum, outcomes, and incidence of ICI-associated toxic effects.ResultsInternationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4).Conclusions and relevanceIn the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Dataset Information

Fatal Adverse Events Associated With Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Publications

Fatal Adverse Events Associated With Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

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