Dataset Information

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

ABSTRACT:

Importance

Immune 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.

Objective

To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.

Design, setting, and participants

We 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.

Exposures

Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab).

Main outcomes and measures

Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects.

Results

Internationally, 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 relevance

In 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.

SUBMITTER: Wang DY

PROVIDER: S-EPMC6440712 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

Wang Daniel Y DY Salem Joe-Elie JE Cohen Justine V JV Chandra Sunandana S Menzer Christian C Ye Fei F Zhao Shilin S Das Satya S Beckermann Kathryn E KE Ha Lisa L Rathmell W Kimryn WK Ancell Kristin K KK Balko Justin M JM Bowman Caitlin C Davis Elizabeth J EJ Chism David D DD Horn Leora L Long Georgina V GV Carlino Matteo S MS Lebrun-Vignes Benedicte B Eroglu Zeynep Z Hassel Jessica C JC Menzies Alexander M AM Sosman Jeffrey A JA Sullivan Ryan J RJ Moslehi Javid J JJ Johnson Douglas B DB

JAMA oncology 20181201 12

<h4>Importance</h4>Immune 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.<h4>Objective</h4>To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.<h4>Design, setting, and participants</h4>We retrospectively queried a World Health Organization (WHO) pharmacovigilance d ...[more]

PMID: 30242316

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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:ImportanceAppropriate clinical decision-making relies on accurate data interpretation, which in turn relies on the use of suitable statistical models. Long tails and early crossover-2 features commonly observed in immune checkpoint inhibitor (ICI) survival curves-raise questions as to the suitability of Cox proportional hazards regression for ICI survival analysis. Cox proportional hazards-Taylor expansion adjustment for long-term survival data (Cox-TEL) adjustment may provide possible solutions in this setting.ObjectiveTo estimate overall survival and progression-free survival benefits of ICI therapy vs chemotherapy using Cox-TEL adjustment.Data sourcesA PubMed search was performed for all cataloged publications through May 22, 2022.Study selectionThe search was restricted to randomized clinical trials with search terms for ICIs and lung cancer, melanoma, or urothelial carcinoma. The publications identified were further reviewed for inclusion.Data extraction and synthesisCox proportional hazards ratios (HRs) were transformed to Cox-TEL HRs for patients with short-term treatment response (ie, short-term survivor) (ST-HR) and difference in proportions for patients with long-term survival (LT-DP) by Cox-TEL. Meta-analyses were performed using a frequentist random-effects model.Main outcomes and measuresOutcomes of interest were pooled overall survival (primary outcome) and progression-free survival (secondary outcome) HRs, ST-HRs, and LT-DPs. Subgroup analyses stratified by cancer type also were performed.ResultsA total of 1036 publications was identified. After 3 levels of review against inclusion criteria, 13 clinical trials (7 in non-small cell lung cancer, 3 in melanoma, and 3 in urothelial carcinoma) were selected for the meta-analysis. In the primary analysis, pooled findings were 0.75 (95% CI, 0.70-0.81) for HR, 0.86 (95% CI, 0.81-0.92) for ST-HR, and 0.08 (95% CI, 0.06-0.10) for LT-DP. In the secondary analysis, the pooled values for progression-free survival were 0.77 (95% CI, 0.64-0.91) for HR, 1.02 (95% CI, 0.84-1.24) for ST-HR, and 0.10 (95% CI, 0.06-0.14) for LT-DP.Conclusions and relevanceThis systematic review and meta-analysis of ICI clinical trial results noted consistently larger ST-HRs vs Cox HRs for ICI therapy, with an LT-DP of approximately 10%. These results suggest that Cox HRs may not provide a full picture of survival outcomes when the risk reduction from treatment is not constant, which may aid in the decision-making process of oncologists and patients.

Dataset Information

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Conclusions and relevance

Publications

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis.

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