Fatal Toxicity With Immunotherapy: Rare, but Increasing

Pam Harrison

September 14, 2018

Fatal toxic effects from immune checkpoint inhibitors (ICIs) are rare, but clinicians need to be aware of the diverse toxic effects that these drugs can have inasmuch as the use of these agents is rapidly increasing, a systematic review and meta-analysis concludes.

"Toxic effects associated with ICIs may affect any organ, and stem from activation of autoreactive T cells damaging host tissues," write the authors, led by Daniel Wang, MD, Vanderbilt University Medical Center, Nashville, Tennessee.

"We report the largest and most comprehensive analysis, to our knowledge, of fatal ICI-associated toxic effects published to date. We found that these events generally occur very early after therapy initiation and with marked distinctions between ICI regimens," they state.

"[T]he 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," the investigators observe.

The study was published online September 13 in JAMA Oncology.

Multiple sources were used to analyze data pertaining to immune-related adverse events (irAEs) associated with ICIs targeting either cytotoxic T lymphocyte antigen–4 (CTLA-4) or programmed cell death–1/ligand-1 (PD-1/PD-L1).

A key source of the data probed was the World Health Organization Vigilyze-Vigibase, which contains more than 16 million reports of individual safety case episodes and adverse drug reactions.

"To avoid capturing cancer-related deaths, we included only reports where known irAEs occurred," Wang and colleagues note.

After screening 3,1059 individual case reports of ICI-related events, the investigators identified 613 fatal irAEs.

The drugs with which these case reports were associated included ipilimumab (Yervoy, Bristol-Myers Squibb) monotherapy (n = 193); PD-1/PD-L1 inhibitors (n = 333), and the combination of a PD-1/PD-L1 inhibitor plus an anti-CTLA-4 agent (n = 87).

"Most patients had a single toxic effect causing death," the investigators observe. Patients who received a combination of ICIs were more likely to have multiple concurrent irAEs than those who received monotherapy, they add.

Importantly, the types of fatal toxic events were highly variable, depending on the regimen used. For example, colitis and diarrhea were prominent when ipilimumab monotherapy was used.

Fatal irAEs seen in association with the PD-1/PD-L1 inhibitors included pneumonitis, hepatitis, colitis, neurologic events, and myocarditis.

Colitis was the most common fatal toxic event associated with combination therapy.

This was followed by myocarditis, hepatitis, pneumonitis, and myositis, the study authors note.

The authors also note that the number of fatal toxic events has greatly increased over time; more than 65% of all deaths from ICIs occurred in 2017 and January of 2018.

Academic Centers

The investigators also reviewed all patients treated with an ICI at seven academic centers.

In this cohort of 3545 patients, the irAE fatality rate was 0.59%. The events were fairly evenly distributed among those treated with ipilimumab, those treated with an anti-PD-1 agent, and those who received a combination of PD-1/CTLA-4 blockade.

In the academic center analysis, "the median time to irAE onset was 15 days following treatment initiation," Wang and colleagues note. "The median time from symptom onset to death was 32 days," they add.

The nature of the event also varied. Cases of irAEs ranged from those that followed a fulminant course with a single hospitalization prior to death (62%) to those that followed a more protracted course in which the patient's condition stabilized and the patient was discharged from hospital before the condition worsened (38%).

An analysis of pooled data from the seven academic centers and those from the Vigilyze database showed that the median time to the onset of a toxic event was relatively early after treatment initiation, at 40 days for ipilimumab, 40 days for the PD-1/PD-L1 inhibitors, and 14.5 days for an ICI combination.

The same analysis showed that for the three regimens, the median time to death was 64 days, 43 days, and 35 days after initiation of treatment, respectively.

Clinical Trial Data

The researchers also analyzed published clinical trial data of the anti-PD-1 agents, the anti-PD-L1 agents, and the anti-CTLA-4 drugs, as well as combinations of these classes of agents.

In 112 trials, 19,217 patients were treated with one or a combination of these agents, and 122 fatal drug-related AEs were documented.

The frequency of fatal toxic events ranged from 0.36% for PD-1 inhibitors, 0.38% for PD-L1 inhibitors, 1.08% for anti-CYLA-4 agents, and 1.23% for the combination of a PD1/PD-L1 plus a CTLA-4 agent.

The authors point out that although the Vigilyze database revealed more than 600 fatal toxic events that were linked to ICI use, "the risk of fatal irAEs remains very low for individual patients with advanced cancer, and should not dissuade use of these potentially curative therapies."

They compared the risk for fatal irAEs associated with ICIs with mortality risks associated with other commonly used oncology agents.

For example, the use of platinum-based doublet chemotherapy is associated with a 0.9% fatality rate, and the fatality rate associated with the use of targeted therapy with either angiogenesis or tyrosine kinase inhibitors ranges from 0 to 4%.

"A treatment-related death rate of 0.36% to 1.23% is dramatically lower than the near-100% fatality rate for metastatic solid tumors," the authors point out.

"Recognizing the timing and spectrum of events is an important new set of concepts that need to be disseminated to the practice community," they conclude.

The study was supported by the Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN), the National Institutes of Health, the James C. Bradford Jr Melanoma Fund, and the Melanoma Research Foundation. Dr Wang has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry, which are detailed in the original article.

JAMA Oncol. Published online September 13, 2018. Full text

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