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Incidence and Outcome of Neurologic Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in
Jack Pepys1, Ronen Stoff1, Roni Ramon-Gonen1
1From the Department of Biomedical Sciences (J.P.), Humanitas University, Milan, Italy; Ella Institute for Immuno-Oncology and Melanoma (R.S., G.B.-B., S.G., R.S.F., J.S., N.A.), Sheba Medical Center; Department of Neurology and Neurosurgery (R.S., G.B.-B., S.G., R.S.F., J.S., N.A., A.T., V.N., A.D.), Sackler Faculty of Medicine, Tel Aviv University; The Graduate School of Business Administration (R.R.-G.), Bar-Ilan University; Department of Neurology (A.T., V.N., A.D.), Sheba Medical Center, Ramat-Gan, Israel; Department of Neurology Mayo Clinic (S.S.), Rochester, MN; Department of Neurology (S.S.), Rambam Medical Center; and Rappaport Faculty of Medicine (S.S.), Technion-Israel Institute of Technology, Haifa, Israel.
Background And Objectives:
Neurologic immune-related adverse events (n-irAEs) reportedly occur in up to 8% of patients treated with immune checkpoint inhibitors (ICIs) of all age groups. We investigated the association between age and n-irAEs in patients treated with ICIs and examined the effect of n-irAEs on survival outcomes in a large cohort of patients with melanoma.
Methods:
We conducted a retrospective analysis of patients with advanced melanoma treated with ICIs at Ella Institute for Immuno-oncology and Melanoma between January 1, 2015, and April 20, 2022. The outcomes of interest were defined as the investigation of age-related frequency and severity of n-irAEs, the need for ICI interruption, the treatment required for n-irAE management, the safety of ICI reintroduction, and n-irAE's effect on survival.
Results:
ICI was administered to 937 patients. At least one irAE occurred in 73.5% (n = 689) of them. Among the study population, 8% (n = 76) developed a n-irAE, with a median age of 66 years in female and 68 years in male patients at onset. The median follow-up after n-irAE was 1,147 days (IQR: 1,091.5 range: 3,938). 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. The 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) was associated with longer survival.
Discussion:
N-irAEs are a relatively common complication of ICIs (8% of our cohort). Older age was not associated with its development or severity, in contrast with non-n-irAEs which occurred less frequently in the elderly population. Rechallenge did not result in life-threatening AEs. Development of any irAEs was associated with longer survival; this association was stronger with n-irAEs.
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