Incidence and Outcome of Neurologic Immune-related Adverse Events Associated with Immune Checkpoint Inhibitors in Patients with Melanoma
Jack (Yaakov) Pepys1, Ronen Stoff2, Roni Ramon-Gonen3, Guy Ben-Betzalel2, Amir Dori4, Shahar Shelly5
1Whipps Cross University Hospital, 2Ella institute for immuno-oncology and Melanoma, Sheba medical center, 3The Graduate School of Business Administration, Bar-Ilan University, Ramat-Gan, Israel, 4Sheba Medical Center, 5Rambam Medical Center
Objective:
To Investigate and characterize Neurological Immune Related Adverse Events (n-irAEs) following cancer immunotherapy as well as age and non-age-related variables impacting survival and treatment outcomes.
Background:
N-irAEs reportedly occur in up to 8% of patients treated with immune-checkpoints inhibitors (ICI), they may be severe and life-threatening and can lead to cancer treatment interruption.
Design/Methods:
We conducted a retrospective analysis of advanced melanoma patients treated with ICI at our institute over a 7-years period. We focused on age-related frequency and severity of n-irAE, ICI interruption, treatment and management, safety of ICI reintroduction, and n-irAE’s impact on overall survival.
Results:
ICI was administered to 937 patients. One or more IrAEs occurred in 73.5% (n=689) of them. Neurological-irAE developed in 8% (n=76), with median age of 66 in females and 68 in males. Median interval from initial ICI treatment to n-irAE development was 48 days across age groups with fewer irAEs occurred in patients older than 70 years (median: 3 events, p=0.04, CI:2.5-4.7). Grade ≥ 3 toxicity manifested in 35.5% of patients. Most common n-irAE phenotypes were myositis (n=34 44.7%), encephalitis (n=8 10.5%), and neuropathy (n=8 10.5%). N-irAE resulted in hospitalization in 40% of patients, and steroids treatment in 46%, median of 4 days from n-irAE diagnosis to steroids treatment initiation. Nine patients needed second-line immunosuppressive treatment. No additional n-irAE was caused by rechallenge in the majority of patients (71%). 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.
Conclusions:
Neurological-irAEs occur relatively frequently in patients treated with ICI (8% of our cohort). Older age was not associated with its development or severity, unlike non-neurological-irAE which occurred less frequently in the elderly. No life-threatening AEs occurred following rechallenge. IrAE development was clearly associated with longer overall survival, this association was even stronger with neurological-irAEs.