Incidence and Outcome of Neurologic Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Patients With Melanoma

Abstract

Background and objectives:Neurological immune related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune-checkpoints inhibitors (ICI) of all age groups. We investigated the association between age and n-irAEs in patients treated with ICI, and examined the impact of n-irAEs on survival outcomes in a large cohort of melanoma patients.Methods:We conducted a retrospective analysis of advanced melanoma patients treated with ICI at Ella Institute for Immuno-oncology and Melanoma between 1/1/2015 and 20/04/2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAE, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE’s impact on survival.Results:ICI was administered to 937 patients. At least one IrAE occurred in 73.5% (n=689) of them. Amongst the study population, 8% (n=76) developed a n-irAE, with a median age of 66 in females and 68 in males at onset. Median follow-up after n-irAE was 1,147 days (IQR: 1091.5 range: 3938). Fewer irAEs occurred in patients older than 70 years (median: 3 events, p=0.04, CI:2.5-4.7), while specifically colitis and pneumonitis were more common in the 18-60 age group (p=0.03 95% CI:0.8,0.38, p=0.009, 95% CI:0.06,0.2). Grade ≥ 3 toxicity was seen in 35.5% of patients across age groups. Median time from ICI administration to n-irAE development was 48 days across age groups. Common n-irAE phenotypes were myositis (44.7%), encephalitis (10.5%), and neuropathy (10.5%). N-irAE required hospitalization in 40% of patients, and steroids treatment in 46% with a median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. Rechallenge did not cause additional n-irAE in 71% of patients. Developing n-irAE (HR=0.4, 95% CI:0.32,0.77) or any irAE (HR=0.7195% CI:0.56,0.88) were associated with longer survival.Discussion:Neurological-irAEs are a relatively common complication of ICI (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-neurological-irAE which occurred less frequently in the elderly. Rechallenge did not result in life-threatening AEs. Development of any irAE was associated with longer survival, this association was stronger with n-irAE.

Neurological Adverse Events Related to Immune Checkpoint Inhibitors: A Practical Review

“…As with other irAEs, ICI re-challenge may lead to a recurrence of symptoms. Retrospective data show a 12–29% recurrence rate after re-exposure to ICI [ 60 , 61 , 62 , 63 ]; however, drawing conclusions is challenging, as clinical outcomes are not always reported.…”