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Fatal Toxic Effects Associated With Immune Checkpoint InhibitorsA Systematic Review and Meta-analysis

Educational Objective
To learn the incidence and types of fatal toxic effects associated with immune checkpoint inhibitors
1 Credit CME
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.


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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Article Information

Corresponding Author: Douglas B. Johnson, MD, Vanderbilt University Medical Center, 2220 Pierce Ave, 777 Preston Research Bldg, Nashville, TN 37232 (douglas.b.johnson@vumc.org).

Accepted for Publication: June 6, 2018.

Correction: This article was corrected on October 11, 2018, to fix the fatality rate percentage for adrenal depicted in Figure 1C.

Published Online: September 13, 2018. doi:10.1001/jamaoncol.2018.3923

Author Contributions: Dr Johnson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wang, Salem, Chandra, Das, Balko, Chism, Long, Hassel, Moslehi, Johnson.

Acquisition, analysis, or interpretation of data: Wang, Salem, Cohen, Menzer, Ye, Zhao, Das, Beckermann, Ha, Rathmell, Ancell, Balko, Bowman, Davis, Horn, Long, Carlino, Lebrun-Vignes, Eroglu, Hassel, Menzies, Sosman, Sullivan, Johnson.

Drafting of the manuscript: Wang, Chandra, Ye, Balko, Long, Menzies, Sosman, Sullivan, Moslehi, Johnson.

Critical revision of the manuscript for important intellectual content: Wang, Salem, Cohen, Menzer, Zhao, Das, Beckermann, Ha, Rathmell, Ancell, Balko, Bowman, Davis, Chism, Horn, Long, Carlino, Lebrun-Vignes, Eroglu, Hassel, Menzies, Sosman, Sullivan, Moslehi, Johnson.

Statistical analysis: Wang, Ye, Zhao, Long, Johnson.

Obtained funding: Rathmell, Johnson.

Administrative, technical, or material support: Salem, Ha, Rathmell, Bowman, Chism, Long, Carlino, Hassel, Menzies, Sullivan, Johnson.

Study supervision: Salem, Menzer, Rathmell, Lebrun-Vignes, Hassel, Moslehi, Johnson.

Conflict of Interest Disclosures: Dr Johnson serves on advisory boards for Array Biopharma, Bristol Myers Squibb, Incyte, Merck, Novartis, and Navigate BP, and receives research funding from Bristol Myers Squibb and Incyte. Dr Rathmell receives research funding from Incyte. Dr Menzies serves on advisory boards for BMS, MSD Merck, Novartis, Roche and Pierre-Fabre. Dr Long serves on advisory boards and steering committees for Amgen, Array Biopharma, Bristol Myers Squibb, Incyte, Merck, Novartis, Pierre-Fabre and Roche. Dr Sosman serves on Advisory Boards for Bristol Myers Squibb, Incyte, Genentech, and Curis. No other disclosures are reported.

Funding/Support: This study was supported by The Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN): “Plan Cancer 2014-2019” (Drs Salem and Lebrun-Vignes) by NIH/NCI K23 CA204726 (Dr Johnson), NIH K24 CA172355 (Dr Rathmell), the James C. Bradford Jr Melanoma Fund (Dr Johnson), and the Melanoma Research Foundation (Dr Johnson).

Role of the Funder/Sponsor: The National Alliance for Life and Health Sciences, National Institutes of Health, the James C. Bradford Jr Melanoma Fund, and the Melanoma Research Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The supplied data from Vigilyze come from a variety of sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the World Health Organization.

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