Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis
Open accessAbstract
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.
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ICI myocarditis occurs in less than 1% of patients.
“Despite occurring in <1% of patients”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [178]
The Multicenter Analysis reports 6 fatal myocarditis cases among 3,545 ICI-treated patients, a rate below 1% for fatal cases. It does not report the incidence of all ICI myocarditis, including nonfatal cases, so it does not establish the claim as stated. (LLM, conf=0.78)
Experimental — accuracy not yet measuredICI myocarditis has a fatality rate of up to 50%.
“ICI myocarditis has a high fatality rate of up to 50%.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [178]
The Global Pharmacovigilance Analysis reports a high fatality rate for ICI-associated myocarditis: 52 deaths among 131 reported cases (39.7%). It does not report a rate of 50%; the Limitations section also cautions that voluntary reporting may overestimate toxicity-specific fatality rates. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCombination therapy with anti-PD-1 and anti-CTLA-4 antibodies is a main risk factor predisposing to ICI myocarditis.
“Combination therapy (eg, anti-PD-1 and anti-CTLA-4 antibodies) and baseline thymus abnormalities, including the primary tumor being thymoma, have been the only main risk factors identified so far predisposing to ICI myocarditis.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [178]
The Global Pharmacovigilance Analysis reports that myocarditis accounted for 22 (25%) combination-therapy deaths, versus 27 (8%) anti-PD-1/PD-L1 monotherapy deaths. These are proportions among reported fatal events, not rates of developing myocarditis; the paper does not establish combination therapy as a main predisposing risk factor. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEndocrine immune-related adverse events, especially adrenal insufficiency, can be life-threatening.
“endocrine irAEs (especially AI) can be life-threatening”
From The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System (2022) · cites this paper as [27]
irAEs affect a broad spectrum of organs, including the colon, liver, lungs, heart, nervous system, skin, and endocrine system.
“These events, which can be severe with combination immunotherapies, affect a broad spectrum of organs, including the colon, liver, lungs, heart, nervous system, skin, and endocrine system.5, 6, 7, 8”
From irAE-GPT: leveraging large language models to identify immune-related adverse events in electronic health records and clinical trial datasets (2026) · cites this paper as [8]
Baseline thymus abnormalities, including the primary tumor being thymoma, are a main risk factor predisposing to ICI myocarditis.
“Combination therapy (eg, anti-PD-1 and anti-CTLA-4 antibodies) and baseline thymus abnormalities, including the primary tumor being thymoma, have been the only main risk factors identified so far predisposing to ICI myocarditis.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [178]
The Global Pharmacovigilance Analysis reports myocarditis among fatal events after combination therapy, but does not identify baseline thymus abnormalities or thymoma as risk factors for developing myocarditis. Searches for thymoma, thymus abnormalities, and myocarditis risk factors found no passage addressing that claim in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredPatients who experienced lethal toxic effects appeared to be older than those not suffering from lethal toxic effects.
“patients who experienced lethal toxic effects appeared to be older than those not suffering from lethal toxic effects [159].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [159]
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Ji, X., Yun, Y., Zhu, Z., Wu, T., Ruan, M., Fan, Y., & Zhang, Q. (2026) · Cancer Cell International · doi:10.1186/s12935-026-04266-7
- Authors
- Wang, D. Y., Salem, J.-E., Cohen, J. V., Chandra, S., Menzer, C., Ye, F., Zhao, S., Das, S., Beckermann, K. E., Ha, L., Rathmell, W. K., Ancell, K. K., Balko, J. M., Bowman, C., Davis, E. J., Chism, D. D., Horn, L., Long, G. V., Carlino, M. S., Lebrun-Vignes, B., Eroglu, Z., Hassel, J. C., Menzies, A. M., Sosman, J. A., Sullivan, R. J., Moslehi, J. J., & Johnson, D. B.
- Affiliations
- Vanderbilt-Ingram Cancer Center (US)
- Inserm (FR)
- Massachusetts General Hospital (US)
- Northwestern University (US)
- Heidelberg University (DE)
- The University of Sydney (AU)
- Department of Pharmacology, Pharmacovigilance Unit, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
- Moffitt Cancer Center (US)
- Corresponding author
- Johnson, Douglas B.
- ORCID
- Wang, Daniel Y.
- Salem, Joe-Elie
- Cohen, Justine V.
- Chandra, Sunandana
- Menzer, Christian
- Ye, Fei
- Zhao, Shilin
- Das, Satya
- Beckermann, Kathryn E.
- Rathmell, W. Kimryn
- Balko, Justin M.
- Bowman, Caitlin
- Davis, Elizabeth J.
- Chism, David D.
- Horn, Leora
- Long, Georgina V.
- Carlino, Matteo S.
- Eroglu, Zeynep
- Hassel, Jessica C.
- Menzies, Alexander M.
- Sosman, Jeffrey A.
- Sullivan, Ryan J.
- Moslehi, Javid J.
- Johnson, Douglas B.
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-12-01
- Volume
- 4
- Issue
- 12
- Pages
- 1721
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6440712
- OpenAlex
- W2891486030
- Cited by
- 2,674
- References
- 26
- Citations by year
- 2026: 296 · 2025: 407 · 2024: 410 · 2023: 369 · 2022: 348 · 2021: 347 · 2020: 336 · 2019: 149 · 2018: 10
- FWCI
- 79.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Melanoma Research Foundation
- Melanoma Research Alliance
- Alliance Nationale pour les Sciences de la Vie et de la Santé
- National Institutes of Health (NIH K24)
- National Cancer Institute (K24CA172355, K23CA204726, K12CA090625, CA204726)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Keywords
- immune checkpoint inhibitors, immune-related adverse events, pneumonitis, colitis, myocarditis, neurotoxicity, hepatotoxicity, PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, ipilimumab, tremelimumab, nivolumab, pembrolizumab, avelumab, durvalumab, atezolizumab
- MeSH terms
- Antineoplastic Agents, Immunological, Humans, Immunologic Factors, Immunotherapy, Neoplasms, Retrospective Studies, Incidence, Databases, Factual, Genes, cdc, Protein Kinase Inhibitors, Pharmacovigilance, Drug-Related Side Effects and Adverse Reactions
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