To rechallenge or not to rechallenge? Immune-checkpoint inhibitor–associated neurotoxicity in advanced melanoma patients.

Abstract

e24187 Background: Immune checkpoint inhibitors (ICIs) are a cornerstone of therapy for treatment of advanced melanoma. Neurotoxicity (N-TOX) is a known complication of ICI therapy with a frequency of 1-5%. Rechallenging with ICIs is traditionally contraindicated after occurrence of N-TOX, however this is a topic of debate, particularly in patients with progression of disease and minimal residual deficits after N-TOX. Methods: We conducted a retrospective study of 28 patients with advanced melanoma (stage 3 or 4) who developed N-TOX after ICI therapy at Moffitt Cancer Center between 2017 and 2025. Variables collected included ICI regimen, ICI duration, N-TOX syndrome, modified Rankin Scale (mRS) at nadir of N-TOX, mRS at 6-months post N-TOX, and median overall survival post N-TOX. If rechallenged with ICI later in disease course, the 6-month mRS and recurrence of N-TOX, if any, was evaluated. Results: All patients (N = 28) had advanced melanoma at onset of ICI therapy (82% stage 4, 18% stage 3). ICI regimens included PD-1 only (N = 8), PD-1/CTLA-4 (N = 16), or PD-1/LAG-3 (N = 4). The median time from start of ICI therapy to onset of N-TOX was 2.4 months (range 0.2-40.3 months). Neurotoxicity syndromes encountered in our cohort included neuropathy (N = 12), myositis (N = 9), cranial neuropathy (N = 4), myasthenia gravis (N = 3), encephalitis (N = 3), transverse myelitis (N = 1), and vasculitis (N = 1). The average N-TOX CTCAE score was 2.9 (range 2-5). Median mRS at nadir of N-TOX was 3 (range 1-6) and median 6-month mRS post N-TOX was 1 (range 0-6). 59% of patients had a 6-month mRS post N-TOX of less than or equal to 1. Median overall survival after N-TOX was 20.2 months (range 0.7-54.1 months). 48% of patients (N = 13) had progression of disease after cessation of ICI therapy. 14% of patients (N = 4, 3 with neuropathy and 1 with cranial neuropathy, mRS nadir range 2-3, all with 6-month mRS post N-TOX of 1) were later rechallenged with ICIs due to progression of disease, with no recurrence of N-TOX noted in any of these patients. Conclusions: N-TOX after ICI therapy in our cohort was usually moderately disabling at nadir, with most patients having minimal residual neurologic deficits at 6-months after N-TOX. ICIs were safely rechallenged in 4 patients in our cohort without N-TOX recurrence, suggesting that ICI rechallenge may be safe in selected patients with progression of disease and minimal residual neurologic disability after N-TOX.