Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Abstract

Background: Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized.

Methods: We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC₀₂₅ (lower end of the IC 95% credibility interval) > 0 is considered statistically significant.

Results: Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5-18.9]; IC₀₂₅ 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC₀₂₅ 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC₀₂₅ 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC₀₂₅ 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping.

Conclusions: ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

Keywords: CTLA-4; Encephalitis; Guillain-Barre syndrome; Myasthenia gravis; Neuropathy; Neurotoxicity; PD-1; PD-L1.

Fig. 1

Information component and its 95% credibility interval over time for (a) neuromuscular junction disorders, (b) encephalitis/myelitis, (c) Guillain-Barre Syndrome, and (d) meningitis

Fig. 2

a Time to event for different categories of neurotoxicities. b Modified Venn diagram showing overlap between distinct classes of neurotoxicities (color scheme the same as in A), as well myositis and myocarditis. Blank cells have no cases for neurotoxicities (e.g. no reports of concurrent myasthenia gravis, GBS, and encephalitis) or were beyond the scope of this study (myositis and myocarditis cases without overlapping neurotoxicities)