Immune checkpoint inhibitor-related neurotoxicity: Incidence and management. A systematic review and meta-analysis

Immune checkpoint inhibitors (ICIs) have improved outcomes for various malignancies. However, serious immune-related adverse events (irAEs), including neurologic complications (NAEs), may occur. The aim of this study was to examine the incidence and spectrum of NAEs and evaluate management strategies for reducing their impact. Two studies were conducted: 1) A meta-analysis of phase I-IV clinical trials involving adults with malignancies treated with ICIs, either as monotherapy, in combination with other ICIs, or with chemotherapy. The primary outcome was the incidence of (ir)NAEs, summarized using a meta-analysis with a random-effects model. 2) A systematic review of the literature addressing the clinical manifestations and treatment of irNAEs. The meta-analysis included 657 unique trials with 91,340 participants. For all ICIs, the incidence of all-grade NAEs was 0.24% (95% CI, 0.15-0.32%). Cerebral events, cerebrovascular accidents, were increased post-treatment and accounted for 54% of all grade-5 events in clinical trials. Among 991 reported irNAE cases, 77% of patients improved with treatment; however, 42% experienced unresolved sequelae and the overall mortality rate was 17.1%. Among patients with overlapping myasthenia gravis, myositis, and myocarditis ("Triple M"), the mortality reached 38%; primarily due respiratory failure (50%) or cardiotoxicity (41%). Although the incidence of ICI-related NAEs is low such side effects may lead to severe morbidity and mortality. In patients with Triple M syndrome intensive respiratory function monitoring and support are essential parameters to improve the outcome. PROSPERO Protocol # CRD42023463750.