To evaluate the late-onset adverse events in a large cohort to better characterize their clinical phenotypes and outcomes.

Immune related adverse events

Retrospective study included patients with late-onset N-irAE, defined as onset ≥ 6 months after ICI initiation. Mayo Clinic patients (2016-2025) underwent extensive testing to rule out mimics. We compared cohorts with intermediate N-irAE onset (1-6 months after ICI initiation), early onset (≤1 month after ICI initiation), performed a time-to-death analysis.

95 N-irAEs, 35 (37%) were late-onset, median age at onset of 66 years (vs 71 in early-onset, P<0.05), female 64% (versus 38% in early-onset, P<0.05). In late-onset N-irAE, 50% of patients had prior radiation and chemotherapy before initiating ICI, compared with 79% in early-onset cases (P<0.05). Median time from cancer diagnosis to ICI initiation was 12 months (IQR 2–48), longer than in early-onset N-irAEs (4 months, IQR 2–31; P<0.05) and intermediate-onset N-irAEs (2 months, IQR 1–8; P<0.05). Eight patients switched ICI classes during treatment (none in the early or intermediate-onset groups; P<0.05). Myopathy was present in 17% of late-onset cases (versus 75% in early-onset, P<0.05); 20% had other peripheral neurological manifestations (vs 3% in early-onset, P<0.05); 14% experienced paraneoplastic neurological syndromes (vs none in early-onset, P<0.05); 6% had fulminant course (vs 30% in early-onset, P<0.05). Nine patients had CNS manifestations other than autoimmune encephalitis/meningitis in late onset (vs 3 each in early/intermediate onset, P<0.05). Mortality from N-irAE was higher in early-onset cases, from myopathy (P<0.05). Deaths from cancer progression were more in late-onset cases, this difference was not statistically significant, due to small sample size. Antibodies in late-onset cohort ANNA-1 (n = 3, one with coexisting NIF), 1 each GAD-65 and AQP4. Intermediate-onset cohort included one each CRMP-5, P/Q channel. 

Late-onset N-irAEs are common, should be recognized with appropriate testing, associated with favorable outcomes compared to early-onset N-irAEs.