Fatal Toxicities Vary by Immune Checkpoint Inhibitor Type

Fatal toxic effects associated with immune checkpoint inhibitors (ICIs) are rare, and their frequency appears to depend on the type of therapeutic regimen, according to a new systematic review and meta-analysis.

Investigators at Vanderbilt University found there are a broad range of regimen-specific toxic effects that can cause fatalities in 0.3% to 1.3% of treated patients. Their findings, published in JAMA Oncology, report that fatal toxic effects tend to occur very early in treatment: at a median of 40 days for monotherapy and of 14.5 days with combination immunotherapy.

“Our study drew on multiple sources to define the clinical features of fatal toxicities associated with ICIs,” said lead study author Daniel Wang, MD, an assistant professor in the department of medicine and hematology/oncology at Baylor College of Medicine in Houston, Texas. “These findings should raise awareness among clinicians of the early and wide-ranging presentation of fatal toxicities.”

The researchers examined the spectrum, timing, and clinical features of fatal ICI-associated toxic effects by examining the World Health Organization’s pharmacovigilance database, VigiLyze. More than 16,000,000 adverse drug reactions and records from 7 academic centers were analyzed. The team also conducted a meta-analysis of published trials with anti–programmed death 1/ligand 1 (PD-1/PD-L1) and anti–cytotoxic T lymphocyte antigen 4 (CTLA-4).

The analysis included anti–CTLA-4 agents (ipilimumab or tremelimumab), anti–PD-1 agents (nivolumab, pembrolizumab), and anti–PD-L1 agents (atezolizumab, avelumab, durvalumab). Using VigiLyze, the researchers found 613 reported fatal toxic events associated with ICIs between 2009 and January 2018.

“It was interesting to find differing patterns of fatal toxicities based on ICI regimens. We noted that deaths related to ipilimumab were largely due to colitis, while deaths related to anti-PD-1 had a broad spectrum of events. Notably, patients treated with combination therapy had more deaths due to co-occurring toxicities (cardiac and neuromuscular),” said Wang.

The retrospective review of 3,545 patients treated with ICIs at 7 academic centers showed there was a 0.6% fatality rate, with cardiac and neurologic events being especially prominent (43%). The median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19,217 patients showed toxicity-related fatality rates were 0.36% with anti–PD-1 treatment, 0.38%  with anti–PD-L1 treatment, 1.08% with anti–CTLA-4 treatment, and 1.23% with a combination of PD-1/PD-L1 and CTLA-4.

“Further molecular studies are needed to understand the underpinning of these fatal events so that algorithms for managing these toxicities can be optimized,” Wang told Cancer Network.

David Gerber, MD, who is a professor of internal medicine in the hematology/oncology division at UT Southwestern Medical Center in Dallas, Texas, stressed the importance of this study in adding to our understanding about the link between immune checkpoint inhibitors and fatal toxicities.

“What sets the autoimmune toxicities of immune checkpoint inhibitors apart from the adverse events of conventional chemotherapy is their unpredictability,” Gerber told Cancer Network. “These toxicities appear to affect patients randomly, with no clear association with cancer type, patient age, or comorbidities.” This study helps to investigate severe immunotherapy toxicities in a more detailed fashion, Gerber added.