From the Journals

Fatal toxicities from checkpoint inhibitors vary by agent



Fatal adverse events are uncommon with immune checkpoint inhibitors (ICI), but they are not unknown, and it’s important to recognize rare, potentially lethal side effects with these agents, investigators say.

A systematic review and meta-analysis of records from academic medical centers and from a pharmacovigilance database found that fatal side adverse events varied in nature and severity according to the agent and immune checkpoint targeted, reported Daniel Y. Wang, MD, of Vanderbilt University Medical Center, Nashville, Tenn., and his colleagues.

“This study underscores that the risk of death associated with complications of ICI therapy is real, but within or well below fatality rates for common oncologic interventions,” they wrote in JAMA Oncology.

In their study, rates of fatal toxic effects associated with immune checkpoint inhibitors ranged from 0.3% to 1.3%. In contrast, the investigators noted, platinum doublet chemotherapy is associated with a 0.9% rate of fatal toxicities, targeted therapies with angiogenesis inhibitors or tyrosine kinase inhibitors have had fatal toxicity rates up to 4%, and allogeneic hematopoietic stem cell transplants are associated with a fatal adverse event rate of approximately 15%. In addition, the death rate associated with complex oncologic surgeries such as the Whipple procedure or esophagectomy ranges from 1% to 10%.

The authors queried the World Health Organization pharmacovigilance database, called Vigilyze, which contains data on more than 16 million adverse drug reactions; records from patients treated with checkpoint inhibitors in seven academic centers in the United States, Germany, and Australia; and published clinical trials.

They combed through the data to identify fatal toxic effects associated with the anti-programmed death 1/ligand-1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), and with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors ipilimumab (Yervoy) and tremelimumab (investigational).

They found in the Vigilyze data that of 193 deaths attributed to CTLA-4 inhibitors, 70% were from colitis, 16% from hepatitis, 8% from pneumonitis, and the remainder from other causes. In contrast, the most common fatal toxicities associated with PD-1/PD-L1 inhibitors were pneumonitis in 35%, hepatitis in 22%, colitis in 17%, and the remainder from other causes.

With the two classes of ICIs used in combination, primarily for treatment of malignant melanoma, colitis accounted for 37% of toxic fatal events, followed by myocarditis in 25%, hepatitis in 22%, pneumonitis in 14%, and others.

The events occurred early in the course of therapy, at a median of 14.5 days from the start of therapy for combination treatment, and 40 days each for anti-PD-1/PD-L1 and anti-CTLA-4 agents.

The complication with highest fatality rate was myocarditis, which killed 39.7% of affected patients. In contrast, endocrine events and colitis were fatal in only 2%-5% of cases. The fatality rates associated with toxic effects in other organ systems ranged from 10% to 17%.

A review of data on 3,545 patients treated with immune checkpoint inhibitors at the seven academic centers found a 0.6% fatality rate, with cardiac and neurologic events accounting for 43% of the deaths.

The investigators also conducted a meta-analysis of data from 112 clinical trials with a total of 19,217 patients treated with ICIs. In these studies, anti-PD-1 agents were associated with a 0.36% rate of fatal toxicities, anti-PD-L1 agents were associated with a 0.38% rate, anti-CTLA-4 agents were linked to a 1.08% rate, and combined PD-1/PD-L1 and CTLA-4 therapy was associated with a 1.23% fatal toxicity rate.

“Each database largely validated the patterns of death from distinct regimens with a few exceptions. Intriguingly, our retrospective analysis at large, experienced academic centers suggested that neurologic and cardiac toxic effects comprised nearly half of deaths. Thus, we surmise that more optimized treatment of these events is urgently needed. In addition, persistent deaths from colitis and pneumonitis, events with standardized treatment algorithms and clear symptoms, suggests that patient and physician education remains a critical objective,” the investigators wrote.

SOURCE: Wang DY et al. JAMA Oncol. 2018 Sept 13. doi: 10.1001/jamaoncol.2018.3923.

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