Immune checkpoint inhibitor neurotoxicity: long-term outcomes with focus on 1-year neurological sequelae

Data on the long-term course of neurological immune-related adverse events (n-irAEs) are limited by the size of studies as well as short and heterogeneous follow-up durations. Herein, we assessed the risk and predictors of 1-year neurological sequelae, and the frequency of n-irAE relapses with or without immune checkpoint inhibitor (ICI) rechallenge.

Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥2 n-irAEs identified in a national reference center were included (2015-2024). Early neurological recovery was defined as CTCAE grade <3 and an improvement of ≥1 point from baseline at 3 months. Long-term sequelae were defined as CTCAE grade ≥2 at 1 year. Associations between prognostic factors and 1-year neurological sequelae were assessed using multivariable logistic regression.

A total of 164 patients were included (median age 69 years, 63% male, median (IQR) follow-up 13 (4-25) months), of whom 59 (36%) had paraneoplastic phenotypes, and 141 (86%) had CTCAE grade 3 or 4 n-irAE at baseline. Most patients (151/163, 93%) received first-line treatments, and 33/163 patients (20%) also received second-line treatments. Early neurological recovery was observed in 82/164 patients (50%). Among 83 patients still alive at 1 year, 33 (40%) had neurological sequelae, and 35 (42%) were receiving treatments. Improvement in CTCAE grade occurred in 13/83 patients (16%) between 3 and 12 months, 1/43 patients (2%) between 12 and 24 months, and it never occurred (0/23) between 24 and 36 months. N-irAE relapses occurred in 25/164 patients (15%), a median (IQR) of 6.8 (3.9-11.8) months after onset. ICI rechallenge led to relapse (CTCAE grade 2) in 1/21 patients (5%). In multivariable analysis, the probability of 1-year neurological sequelae was higher in patients with paraneoplastic phenotypes (OR 11.09, 95% CI (3.24 to 44.51)) and in those who had a relapse within 9 months from baseline (OR 11.12, 95% CI (2.13 to 89.53)).

Paraneoplastic phenotypes and relapses increase the risk of neurological sequelae among long-term n-irAE survivors, and ICI rechallenge might be safe in n-irAE patients who have fully recovered. The rarity of recovery and low risk of relapse after 1 year suggest that prolonged immunosuppression may be unnecessary, but prospective studies are needed to refine management strategies.