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Original Investigation
December 2018

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

Author Affiliations
  • 1Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 2Department of Pharmacology, Pharmacovigilance Unit, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
  • 3INSERM, UMR ICAN 1166, Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
  • 4Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
  • 5Robert H. Lurie Cancer Center, Department of Medicine, Northwestern University Medical Center, Chicago, Illinois
  • 6National Center for Tumor Diseases, Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany
  • 7Vanderbilt Ingram Cancer Center, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 8Melanoma Institute of Australia, Sydney, New South Wales, Australia
  • 9University of Sydney, Sydney, New South Wales, Australia
  • 10Royal North Shore Hospital, Sydney, New South Wales, Australia
  • 11Mater Hospital, Sydney, New South Wales, Australia
  • 12Department of Medical Oncology, Westmeade Hospital, Sydney, New South Wales, Australia
  • 13Department of Medical Oncology, Blacktown Hospital, Sydney, New South Wales, Australia
  • 14Department of Cutaneous Oncology, The Moffitt Cancer Center and Research Institute, Tampa, Florida
JAMA Oncol. 2018;4(12):1721-1728. doi:10.1001/jamaoncol.2018.3923
Key Points

Question  What are the spectrum, timing, and incidence of fatal toxic effects associated with immune checkpoint inhibitors?

Findings  A broad range of regimen-specific toxic effects caused fatalities in 0.3% to 1.3% of treated patients; fatal toxic effects tended to occur very early in treatment (median of 40 and 14.5 days for monotherapy and combination immunotherapy, respectively).

Meaning  Fatal toxic effects from immune checkpoint inhibitors are rare but have diverse causes; awareness is needed among clinicians across disciplines given the increase in use of these agents.

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.

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