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

Daniel Y. Wang, Joe Elie Salem, Justine V. Cohen, Sunandana Chandra, Christian Menzer, Fei Ye, Shilin Zhao, Satya Das, Kathryn E. Beckermann, Lisa Ha, W. Kimryn Rathmell, Kristin K. Ancell, Justin M. Balko, Caitlin Bowman, Elizabeth J. Davis, David D. Chism, Leora Horn, Georgina V. Long, Matteo S. Carlino, Benedicte Lebrun-VignesZeynep Eroglu, Jessica C. Hassel, Alexander M. Menzies, Jeffrey A. Sosman, Ryan J. Sullivan, Javid J. Moslehi, Douglas B. Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticle

121 Citations (Scopus)

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 16000000 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 19217 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.

Original languageEnglish (US)
Pages (from-to)1721-1728
Number of pages8
JournalJAMA Oncology
Volume4
Issue number12
DOIs
StatePublished - Dec 2018

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CTLA-4 Antigen
Poisons
Meta-Analysis
Colitis
Pharmacovigilance
Myocarditis
Fatal Outcome
Incidence
Therapeutics
Secondary Prevention
Drug-Related Side Effects and Adverse Reactions
Nervous System
Hepatitis
Neoplasms
Pneumonia
Outcome Assessment (Health Care)
Clinical Trials
Databases
Ligands
Thomsen-Friedenreich antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, Daniel Y. ; Salem, Joe Elie ; Cohen, Justine V. ; Chandra, Sunandana ; Menzer, Christian ; Ye, Fei ; Zhao, Shilin ; Das, Satya ; Beckermann, Kathryn E. ; Ha, Lisa ; Rathmell, W. Kimryn ; Ancell, Kristin K. ; Balko, Justin M. ; Bowman, Caitlin ; Davis, Elizabeth J. ; Chism, David D. ; Horn, Leora ; Long, Georgina V. ; Carlino, Matteo S. ; Lebrun-Vignes, Benedicte ; Eroglu, Zeynep ; Hassel, Jessica C. ; Menzies, Alexander M. ; Sosman, Jeffrey A. ; Sullivan, Ryan J. ; Moslehi, Javid J. ; Johnson, Douglas B. / Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors : A Systematic Review and Meta-analysis. In: JAMA Oncology. 2018 ; Vol. 4, No. 12. pp. 1721-1728.
@article{2303f7fc50f741349529dc0f8d003bee,
title = "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 16000000 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 19217 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.",
author = "Wang, {Daniel Y.} and Salem, {Joe Elie} and Cohen, {Justine V.} and Sunandana Chandra and Christian Menzer and Fei Ye and Shilin Zhao and Satya Das and Beckermann, {Kathryn E.} and Lisa Ha and Rathmell, {W. Kimryn} and Ancell, {Kristin K.} and Balko, {Justin M.} and Caitlin Bowman and Davis, {Elizabeth J.} and Chism, {David D.} and Leora Horn and Long, {Georgina V.} and Carlino, {Matteo S.} and Benedicte Lebrun-Vignes and Zeynep Eroglu and Hassel, {Jessica C.} and Menzies, {Alexander M.} and Sosman, {Jeffrey A.} and Sullivan, {Ryan J.} and Moslehi, {Javid J.} and Johnson, {Douglas B.}",
year = "2018",
month = "12",
doi = "10.1001/jamaoncol.2018.3923",
language = "English (US)",
volume = "4",
pages = "1721--1728",
journal = "JAMA oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "12",

}

Wang, DY, Salem, JE, Cohen, JV, Chandra, S, Menzer, C, Ye, F, Zhao, S, Das, S, Beckermann, KE, Ha, L, Rathmell, WK, Ancell, KK, Balko, JM, Bowman, C, Davis, EJ, Chism, DD, Horn, L, Long, GV, Carlino, MS, Lebrun-Vignes, B, Eroglu, Z, Hassel, JC, Menzies, AM, Sosman, JA, Sullivan, RJ, Moslehi, JJ & Johnson, DB 2018, 'Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis', JAMA Oncology, vol. 4, no. 12, pp. 1721-1728. https://doi.org/10.1001/jamaoncol.2018.3923

Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors : A Systematic Review and Meta-analysis. / Wang, Daniel Y.; Salem, Joe Elie; Cohen, Justine V.; Chandra, Sunandana; Menzer, Christian; Ye, Fei; Zhao, Shilin; Das, Satya; Beckermann, Kathryn E.; Ha, Lisa; Rathmell, W. Kimryn; Ancell, Kristin K.; Balko, Justin M.; Bowman, Caitlin; Davis, Elizabeth J.; Chism, David D.; Horn, Leora; Long, Georgina V.; Carlino, Matteo S.; Lebrun-Vignes, Benedicte; Eroglu, Zeynep; Hassel, Jessica C.; Menzies, Alexander M.; Sosman, Jeffrey A.; Sullivan, Ryan J.; Moslehi, Javid J.; Johnson, Douglas B.

In: JAMA Oncology, Vol. 4, No. 12, 12.2018, p. 1721-1728.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors

T2 - A Systematic Review and Meta-analysis

AU - Wang, Daniel Y.

AU - Salem, Joe Elie

AU - Cohen, Justine V.

AU - Chandra, Sunandana

AU - Menzer, Christian

AU - Ye, Fei

AU - Zhao, Shilin

AU - Das, Satya

AU - Beckermann, Kathryn E.

AU - Ha, Lisa

AU - Rathmell, W. Kimryn

AU - Ancell, Kristin K.

AU - Balko, Justin M.

AU - Bowman, Caitlin

AU - Davis, Elizabeth J.

AU - Chism, David D.

AU - Horn, Leora

AU - Long, Georgina V.

AU - Carlino, Matteo S.

AU - Lebrun-Vignes, Benedicte

AU - Eroglu, Zeynep

AU - Hassel, Jessica C.

AU - Menzies, Alexander M.

AU - Sosman, Jeffrey A.

AU - Sullivan, Ryan J.

AU - Moslehi, Javid J.

AU - Johnson, Douglas B.

PY - 2018/12

Y1 - 2018/12

N2 - 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 16000000 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 19217 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.

AB - 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 16000000 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 19217 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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