ICI-Related Fatal Toxicities Are Rare, Appear Early in Treatment


Immune checkpoint inhibitor-related toxic events led to deaths in 0.3% to 1.3% of patients, a rate that compares favorably with other treatment modalities, according to results from a retrospective analysis of data collected in Vigilyze, the World Health Organization’s pharmacovigilance database.

Douglas B. Johnson, MD

Douglas B. Johnson, MD

Immune checkpoint inhibitor (ICI)-related toxic events led to deaths in 0.3% to 1.3% of patients, a rate that compares favorably with other treatment modalities, according to results from a retrospective analysis of data collected in Vigilyze, the World Health Organization’s pharmacovigilance database.

Corresponding author Douglas B. Johnson, MD, assistant professor of medicine and clinical director of the Melanoma Research Program at Vanderbilt-Ingram Cancer Center, and colleagues wrote that the incidence of fatal toxicities was similar to or lower than the rates associated with treatments like targeted therapy with angiogenesis or tyrosine kinase inhibitors (0%-4%), allogeneic stem cell transplant (approximately 15%), platinum-doublet chemotherapy (0.9%), and complex oncology surgeries such as Whipple procedure or esophagectomy (1%-10%). The investigators noted that despite the high number of fatal deaths reported, the benefit-risk profile still favors the use of ICIs.

“Despite the impressive number of fatal events reported (>600 in Vigilyze), the risk of fatal immune-related adverse events remains very low for individual patients with advanced cancer, and should not dissuade use of these potentially curative therapies,” Johnson et al concluded. “Instead, the global increase in ICI use across cancer types highlights the importance of defining the most serious toxic effects and developing awareness among oncologists, emergency department physicians, critical care providers, and other specialists.”

From 2009 to January 2015, 613 fatal toxic events related to ICIs from 31,059 case reports were entered into the database. Eight-seven patients were treated with a combination of anti—PD-1/PD-L1 plus anti–CTLA-4, 193 received anti–CTLA-4 treatment with single-agent ipilimumab (Yervoy), and 333 received anti–PD-1/PD-L1 therapy.

Melanoma was the most common disease treated with ipilimumab either alone (96%) or in combination (66%). Patients were most likely to be assigned to anti—PD-1/PD-L1 for lung cancer (54%), melanoma (18%), or genitourinary cancers (10%).

Colitis/diarrhea was the most common fatal toxicity among patients receiving ipilimumab monotherapy (70%; n = 135), followed by hepatitis (16%; n = 31), and pneumonitis (8%; n = 15). Pneumonitis was the most common fatal toxicity in patients receiving anti—PD-1/PD-L1 therapy (35%; n = 115), followed by hepatitis (22%; n = 74) and colitis (17%; n = 58).

Colitis was the most common fatal adverse event (AE) among those receiving combination therapy (37%; n = 32). Hepatitis (22%; n = 19) and pneumonitis (14%; n = 12) were also frequent causes of death, as were myocarditis (25%; n = 22) and myositis (13%; n = 11), which frequently appeared together.

Investigators assessed fatality rates for different classes of AEs to determine the risk for fatality associated with specific toxic effects. With 52 deaths among 131 reported AEs, myocarditis was associated with the highest risk for death (39.7%). The death rates for pneumonitis, hepatitis, nephritis, myositis, hematologic, and neurologic AEs ranged from 10% to 17% of reported cases. Investigators observed the lowest rates in colitis (5%), adrenal insufficiency (3.7%), and hypophysitis (2%).

“We observed variable patterns among ICI regimens. Ipilimumab deaths were dominated by colitis, whereas anti-PD—1 had a wide spectrum of events,” Johnson et al wrote. “Combination therapy had more frequent multiorgan involvement, and nearly one-third of all deaths were from myocarditis, myositis, and/or neurologic events. Hepatitis accounted for about 20% of deaths in each cohort.”

A single toxic event was the cause of most deaths. Multiple concurrent AEs were more likely to appear in patients assigned to anti—PD-1/PD-L1 plus anti–CTLA-4 (27%) compared with anti–PD-1/PD-L1 (15%) or ipilimumab (14%).

Investigators found that the types of fatal AEs remained consistent over time, though there was an increase in myocarditis across all regimens. However, fatal AEs became more prevalent over time, as more than 65% of reported deaths occurred in 2017 and January 2018.

Johnson et al found 21 fatal AEs in an analysis of 3545 (0.59%) patients treated at 7 international academic centers. Seven patients had received ipilimumab, 9 had received anti—PD-1, and 5 received combination PD-1/DTLA-4 blockade.

Onset of immune-related AEs occurred at a median of 15 days (range, 3-543 days) following the beginning of treatment. Eleven (52%) patients developed immune-related AEs within 20 days. Death occurred at a median of 32 days (range, 3-355 days) from symptom onset.

The median patient age was 72 years (range, 37-84). Investigators found that patients who died of AEs tended to be older (70 vs 62 years;P= .009).

Johnson et al then reviewed safety data collected in clinical trials evaluating anti—PD-1 regimens (nivolumab [Opdivo] and pembrolizumab [Keytruda]), anti–PD-L1 regimens (atezolizumab [Tecentriq], avelumab [Bavencio], and durvalumab [Imfinzi]), anti–CTLA-4 regimens (ipilimumab [Yervoy] and tremelimumab), and PD-1/PD-L1/CTLA-4 inhibition combinations. There were 122 drug-related deaths recorded in these 112 trials involving 19,217 patients.


Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis [published online September 9, 2018].JAMA Oncol. doi:10.1001/jamaoncol.2018.3923.

Combination regimens accounted for 1.23% of patient deaths compared with 1.08% for CTLA-4, 0.38% for PD-L1, and 0.36% for PD-1. Incidence of fatal AEs was lower for patients assigned to PD-1/PD-L1 inhibitors compared with either CTLA-4 monotherapy or combination therapy (&chi;2 = 58.8;P<.001). Investigators observed no difference in incidence between anti-CTLA-4 monotherapy and combination therapy (&chi;2 = 0.23;P= .62) or between PD-1 and PD-L1 inhibitors (&chi;2 = 0.021;P= .88).

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