To evaluate outcomes of rechallenge with immune checkpoint inhibitors (ICIs) following neurologic immune-related adverse events (irAE-Ns). 

ICIs have transformed cancer treatment, however, side effects called irAEs may occur due to off-target autoimmunity. irAE-N incidence is 1-12% and approximately 28% are fatal. Safety of ICI re-challenge after irAE-Ns is poorly understood.

We performed a systematic review using MEDLINE, Embase, and Web of Science screening English-language papers including case reports/series, cohort studies and clinical trials. For inclusion, patients 1) were ≥ 18 years old with cancer; 2) had received ≥ 1 ICI; 3) developed ≥ 1 irAE-N; and 4) received ICI rechallenge. Two reviewers screened articles using the Covidence review software and identified eligible patients. We used consensus disease definitions for irAE-N classification and severity grading (grade 1 = mild to grade 5 = death). 

Eighty-three patients from 21 papers were included. Of 53/83 (64%) in whom a specific irAE-N was described, the peripheral nervous system was affected in 30/53 (57%) and central nervous system (CNS) in 23/53 (43%). irAE-N subtypes were irMyopathy (N=21, 40%), irMeningitis (N=11, 21%), irEncephalitis (N=9, 17%), irNeuropathy (N=5, 9%), irNeuromuscular junction disorder (N=4, 7%), irDemyelinating disorder (N=1, 2%), irVasculitis (N=1, 2%), and other CNS (N=1, 2%). Of 29 patients with irAE-N severity reported, 18 (62%) had grade 1 or 2; 11 (38%), grade 3 or 4. With rechallenge, 16/83 (19%) experienced a second irAE-N and 6/83 (7%), an irAE affecting another organ. Treatment of irAE-Ns was described in 27/83 (32%). 21/27 (78%) received oral or intravenous corticosteroid monotherapy. Of 5 deaths, 4 resulted from cancer progression and 1 from sepsis with median follow-up 15 months [IQR 9-24].

ICI rechallenge following irAE-Ns showed a recurrence rate of 19% with no deaths from second irAE-N. Data reporting gaps were identified. Prospective study of ICI rechallenge after irAE-N is needed.