To characterize the severity, progression, chronicity and treatment of ICI-induced N-Tox in a standard of care (SOC) setting.

ICI-induced N-Tox is understudied despite its morbidity and potential mortality. Our previous report on melanoma patients enrolled in ICI phase III clinical trials revealed that 32% of patients with mild/non-specific symptoms progressed to more severe N-Tox, and in some cases required hospitalization. However, the management information of N-Tox and long-term outcomes were unavailable, and the high rate of progression has not previously been studied in SOC setting.

We conducted a single institution study of melanoma patients enrolled in a prospective database who received ICI as SOC and developed N-Tox. We analyzed their clinical manifestations, treatment outcomes, laboratory, neuroimaging, and electrophysiologic data.

89/666 (13%) patients developed N-Tox (G1:33, G2:31, G3:18, G4:4) ranging from 2% with ipilimumab, 5% with nivolumab+relatlimab, 9% with pembrolizumab, 14% with nivolumab, and 15% with ipilimumab+nivolumab. Peripheral neuropathy and myopathy were the most common N-Tox. 49(55%) patients initially presented with mild non-specific neurological symptoms and 27(30%) progressed to more severe N-Tox. 46(51%) required ICI discontinuation or interruption and 20(22%) were hospitalized. 38(43%) patients received corticosteroids and 5(6%) required IVIG, PLEX, or rituximab. Median time to N-Tox resolution was 53 days, however, 30(33%) patients had persistent symptoms >3 months. Grade≥2 N-Tox was significantly associated with chronicity (p=0.02, OR=2.98). Among N-Tox patients with available laboratory results, 24/31(77%) had elevated ESR, 22/36(61%) had elevated CRP, 6/12(50%) had elevated ANA, 8/8(100%) had elevated CSF protein and glucose; EMGs for patients with peripheral neuropathy showed axonal (4/11), demyelinating (1/11), and mixed neuropathy (3/11). 

Our data demonstrate frequent progression of mild/nonspecific symptoms to more severe N-Tox, leading to treatment disruptions, hospitalization and substantial chronicity. Thus, early identification and management of N-Tox in ICI-treated patients, and the need for standardized management in the prospective setting is crucial.