Adverse neurologic events of immune checkpoint inhibitor monotherapy vs. combination therapy for melanoma

Over the past decade, novel immune checkpoint inhibitors have revolutionized melanoma treatment. These new therapies are associated with complex immune-related adverse events. This study examines whether combination anti-PD-1/CTLA-4 immunotherapy for melanoma is associated with increased incidence of neurologic irAEs (n-irAEs) compared to anti-PD-1 monotherapy.

A retrospective, multicenter study using TriNetX identified adult melanoma patients receiving anti-PD-1 monotherapy (pembrolizumab or nivolumab) (Cohort 1: n = 10,586) and patients receiving anti-PD-1/CTLA-4 combination therapy (nivolumab + ipilimumab) (Cohort 2: n = 5,705). Propensity score matching generated final cohorts (n = 5,185) using covariates: gender, race, age at diagnosis, TNM staging, nervous system metastasis, and history of neurologic disease. Odds ratios (OR) for n-irAE subtypes at 3- and 5-year post-therapy initiation were calculated, and Kaplan-Meier analyses assessed overall survival by aggregate n-irAE status in each cohort.

At 3 years, patients receiving combination immunotherapy exhibited increased risk of immune-related meningitis (OR: 2.6, 95% CI: [1.7, 4.1]) and encephalitis (OR: 3.0, 95% CI: [1.9, 4.9]), peripheral neuropathy (OR: 1.3, 95% CI [1.1, 1.5]), and myopathy (OR: 1.5, 95% CI: [1.1, 2.1]), but no significantly increased risk of demyelinating syndromes (OR: 1.5, 95% CI: [0.82, 2.6]), vasculitis (OR: 0.88, 95% CI: [0.43, 1.8]), or neuromuscular junction disorders (OR: 1.3, 95% CI: [0.87, 2.0]). At 5 years, these trends for risk of neurologic irAEs persisted. There was no significant difference in overall survival by n-irAE presence at 3 or 5 years in either cohort.

Melanoma patients receiving combination anti-PD-1/CTLA-4 immunotherapy have greater long-term risk of n-irAEs than patients receiving anti-PD-1 monotherapy.