Fatal toxic events possible, but rare, with immune checkpoint inhibitors

Douglas B. Johnson

Fatal toxic events occurred in about 0.3% to 1.3% of patients treated with immune checkpoint inhibitors, according to a meta-analysis of adverse outcomes reports and trial data.

These event rates compare favorably with other oncologic interventions.

“Immune checkpoint inhibitors stimulate immune cells to attack cancer, but they may accidentally target our own tissue,” Douglas B. Johnson, MD, assistant professor of medicine and clinical director of the melanoma research program at Vanderbilt University Medical Center, told HemOnc Today. “This can lead to side effects which are usually manageable with steroid treatment. However, we have occasionally seen side effects that were severe enough to cause death.

“We wanted to study these most serious toxicities, in terms of which organs were affected, what is their timing and how often they occur,” he added.

Johnson and colleagues used data from VigiLyze — a WHO pharmacovigilance database that includes more than 16 million adverse drug reactions — to assess fatal toxic events among patients treated with immune checkpoint inhibitors.

The analysis included patients treated with:

  • anti-CTL-4 therapies ipilimumab (Yervoy, Bristol-Myers Squibb) or tremelimumab (MedImmune/AstraZeneca);
  • anti-PD-1 therapies nivolumab (Opdivo, Bristol-Myers Squibb) or pembrolizumab (Keytruda, Merck); or
  • anti-PD-L1 therapies atezolizumab (Tecentriq, Genentech), avelumab (Bavencio; EMD Serono, Pfizer) or durvalumab (Imfinzi, AstraZeneca).

From 2009 through January 2018, 613 fatal immune checkpoint inhibitor-related toxic events were reported internationally. Of these, 193 occurred among patients treated with anti-CTLA-4 agents, 333 among those who received anti-PD-1 and anti-PD-L1 therapies, and 87 among those who received a combination of these therapies.

Exclusion criteria included resolving toxic effects, unknown outcomes or known/presumed cancer-related deaths.

Seventy percent of fatal toxic events associated with anti-CTLA-4 therapies were from colitis.

Among patients treated with anti-PD-1 and anti-PD-L1 therapies, deaths were most often related to pneumonitis (35%), hepatitis (22%) and neurotoxic effects (15%).

Among those treated with combination anti-CTLA-4 and anti-PD-1/PD-L1 therapies, colitis (37%) and myocarditis (25%) caused most deaths.

Fatal toxic effects usually occurred early after therapy initiation. Median time to toxic effect was 14.5 days among those treated with combination therapy and 40 days among those treated with anti-PD-1 or ipilimumab monotherapy.

Of the reported toxic events, myocarditis had the highest fatality rate — 39.7% — compared with organ-system toxic effects (10% to 17%) and endocrine events and colitis (2% to 5%).

“Fatal side effects are rare with immune checkpoint inhibitors and compare favorably to other cancer treatments,” Johnson said. “However, clinicians should be aware that these toxicities can be fatal and be vigilant for them. The most serious toxicities commonly affect the heart, lungs, colon and liver, but may also affect other organs, and tend to occur early on therapy — on average during the first 6 weeks of treatment.”

In an additional retrospective analysis of 3,545 patients treated with immune checkpoint inhibitors across seven academic centers, researchers observed a fatality rate of 0.6%. Cardiac and neurologic events occurred among 43% of patients.

A meta-analysis of 19,217 patients across 112 trials showed fatality rates of:

  • 0.36% among patients treated with anti-PD-1;
  • 0.38% among patients treated with anti-PD-L1;
  • 1.08% among patients treated with anti-CTLA-1; and
  • 1.23% among patients treated with combination therapy.

“Early recognition and prompt steroid treatment are important,” Johnson said. “If patients are not improving on steroids, other immune-suppressive drugs should be considered. A high index of suspicion is very important, because these side effects can affect almost any organ and may mimic other conditions.”

The limitations of the study included the rarity of the events, lack of detailed clinical data and the voluntary nature of reporting events to the VigiLyze database. – by Cassie Homer

For more information:

Douglas B. Johnson, MD, can be reached at Vanderbilt University Medical Center, 2220 Pierce Ave., 777 Preston Research Bldg, Nashville, TN; email: douglas.b.johnson@vumc.org.

Disclosures: Johnson reports advisory board roles with Array Biopharma, Bristol-Myers Squibb, Incyte, Merck, Navigate BP and Novartis, and research funding from Bristol-Myers Squibb and Incyte. Please see the study for all other authors’ relevant financial disclosures.

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