Immune Checkpoint Inhibitors Increase Risk of Neurologic Toxicities

Treatment with immune checkpoint inhibitors (ICIs) is associated with an increased risk of neurologic toxicities, with combination use of ICIs conferring a higher risk of some neurologic complications compared with monotherapy, according to research to be presented at the American Academy of Neurology 2021 Virtual Annual Meeting, to be held April 17 to 22, 2021.

The retrospective observational study relied on data from the FAERS database, collected from 2014 to 2019. Study investigators examined the rate of ICI-related adverse events (AEs), defined as adverse reactions reported in patients treated with anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab) agents.

Additionally, the study investigators evaluated in the disproportionality analysis the neurologic AEs previously reported to be associated with ICIs.

A total of 3619 neurologic cases were found in the 50,406 reports of ICI-related AEs.

There were 1985 neurologic AEs with anti-PD-1, accounting for 6.10% of anti-PD-1-related AEs, as well as 372 neurologic AEs with anti-PD-L1, accounting for 5.26% of anti-PD-L1-related AEs. A total of 366 neurologic AEs were reported with anti-CTLA-4, or 12.7% of anti-CTLA-4-related AEs, and 896 with a combination of anti-CTLA-4 with anti-PD-1 or anti-PD-L1 (11.3% of combined ICI-related AEs).

Compared with nonICI drug use, treatment with ICI was associated with an increased risk for neurologic complications, including hypophysitis or hypopituitarism (reporting odds ratio [ROR], 207.14; 95% CI, 176.44-243.19]), myasthenia gravis (ROR, 23.28; 95% CI, 20.28-26.73), vasculitis (ROR, 1.49; 95% CI, 1.20-1.84), neuropathy (ROR, 1.08; 95% CI, 1.02-1.15), Guillain-Barre syndrome (ROR, 5.15; 95% CI, 3.97-6.70), meningitis (ROR, 5.71; 95% CI, 4.75-6.86), and encephalitis or myelitis (ROR, 14.15; 95% CI, 12.59-15.91).

In contrast, treatment with ICU was associated with a reduced risk of demyelinating disorders (ROR, 0.51; 95% CI, 0.41-0.63).

Combination use of ICIs correlated with a higher risk of hypopituitarism, hypophysitis, neuropathy, Guillain-Barre syndrome, meningitis, encephalitis, and myelitis compared with monotherapy. Despite this increased risk, the study investigators noted that “the proportion of serious neurological events related to combination therapy has been decreasing in recent years.”

Reference

Mikami T, Liaw B, Asada M, et al. Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database. J Neurooncol. 2021;152(1):135-144. doi:10.1007/s11060-020-03687-2