Uncommon Lethal Complications of Immune Checkpoint Inhibitors


Key Points

  • In the WHO database, the greatest risk of fatality appeared to be associated with myocarditis.
  • In meta-analysis of clinical trials, ICI-related fatality rates were 0.36% for anti–PD-1, 0.38% for anti–PD-L1, 1.08% for anti–CTLA-4, and 1.23% for PD-1/PD-L1 plus CTLA-4 treatment.


In a systematic review and meta-analysis reported in JAMA Oncology, Wang et al identified frequency and types of fatal toxic effects in patients receiving immune checkpoint inhibitor therapy.

Study Details

The study involved analysis of fatal immune checkpoint inhibitor–associated toxic effects identified in a WHO pharmacovigilance database (VigiLyze)—including more than 16,000,000 reported adverse drug reactions—and records from 7 academic centers (Vanderbilt-Ingram Cancer Center, Massachusetts General Hospital, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Melanoma Institute of Australia, Westmead Hospital, National Center for Tumor Diseases Heidelberg, and Moffitt Cancer Center). A meta-analysis was performed for published trials of anti–programmed cell death protein 1/ligand-1 (PD-1 [nivolumab (Opdivo), pembrolizumab (Keytruda)]/PD-L1 [atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi)]) and anti–cytotoxic T lymphocyte antigen-4 (CTLA-4 [ipilimumab (Yervoy), tremelimumab]) agents.

Immune Checkpoint Inhibitor–Related Fatalities

According to the VigiLyze database, 613 fatal immune checkpoint inhibitor toxic events were reported from 2009 through January 2018. These included 193 deaths related to ipilimumab, with the majority (135, 70%) due to colitis. Among 333 anti–PD-1/PD-L1–related fatalities, most were associated with pneumonitis (115, 35%), hepatitis (74, 22%), and neurotoxic effects (50, 15%). Among 87 combination PD-1/CTLA-4 deaths, most were due to colitis (32, 37%) and myocarditis (22, 25%). Fatality due to toxic effects occurred at medians of 64, 43, and 35 days after start of treatment for ipilimumab, anti–PD-1/PD-L1, and combination treatment. Observed risk of death appeared to be highest with myocarditis, occurring in 52 (39.7%) of 131 cases. Pneumonitis, hepatitis, myositis, nephritis, neurologic, and hematologic toxicities were associated with fatalities in 10% to 17% of cases. Hypophysitis, adrenal insufficiency, and colitis were associated with fatalities in 2% to 5% of cases.

In the review of 3,545 patients treated with immune checkpoint inhibitors at 7 academic centers (91% with melanoma), immune checkpoint inhibitor–related fatality occurred in 21 patients (0.6%). Cardiac and neurologic events accounted for 43% of fatalities. Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19,217 patients indicated immune checkpoint inhibitor–related fatality rates of 0.36% for anti–PD-1, 0.38% for anti–PD-L1, 1.08% for anti–CTLA-4, and 1.23% for PD-1/PD-L1 plus CTLA-4 treatment.

The investigators concluded, “In the largest evaluation of fatal immune checkpoint inhibitor–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.”

This study was supported by The Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN), the U.S. National Cancer Institute and National Institutes of Health, James C. Bradford Jr Melanoma Fund, and Melanoma Research Foundation.

Douglas B. Johnson, MD, of Vanderbilt University Medical Center, is the corresponding author for the JAMA Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.