Anti-PD-1 Therapy and Long-Term Toxic Effects Among Patients With Melanoma.

Importance: Adjuvant anti-programmed cell death protein 1 (anti-PD-1) treatment improves outcomes in high-risk resected melanoma but causes chronic immune-related adverse events (irAEs) in more than 40% of patients. Risk factors associated with chronic vs acute irAEs remain lacking. Objective: To identify factors and possible candidate inflammatory pathways associated with the development of chronic nonendocrine irAEs. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2015, to December 31, 2024, at 7 institutions in the US and Australia. Patients had stage III to IV melanoma treated with adjuvant anti-PD-1 therapy and more than 12 months of follow-up after discontinuation of anti-PD-1 treatment. Exposures: Potential risk factors (age, sex, time to irAE onset, corticosteroid exposure, time to corticosteroid initiation, peak corticosteroid dose, and anti-PD-1 treatment status) for chronic irAEs. Main Outcomes and Measures: Incidence, type, and risk factors for chronic (persisting ≥3 months after anti-PD-1 therapy cessation) irAEs and cytokine levels at 12 months after immune checkpoint inhibitor initiation were assessed. Results: Among 303 patients (median age at anti-PD-1 therapy initiation, 64 years [IQR, 55-72 years]; 184 men [61%]), 220 (73%) developed acute irAEs and 146 (48%) developed chronic irAEs. The most common chronic irAEs were hypothyroidism (45 of 146 [31%]), arthritis (25 of 146 [17%]), and dermatitis (17 of 146 [12%]). Chronic irAEs had later onset (median, 153.0 days [IQR, 67.0-294.0 days] vs 99.0 days [IQR, 32.2-228.8 days]; P = .006) and more frequent corticosteroid exposure (35% [34 of 96] vs 24% [48 of 204]; P = .03) compared with nonchronic irAEs. For exploratory risk factor analysis of 300 nonendocrine irAE events, corticosteroid treatment and onset time had a significant interaction; corticosteroid-treated patients with earlier-onset irAEs had higher odds of developing chronic irAEs (odds ratio, 3.00; 95% CI, 1.45-6.22), adjusted for age, sex, and anti-PD-1 therapy continuation. Eight different cytokines had higher circulating plasma levels among patients with chronic irAEs after false discovery rate (FDR) adjustment (including VEGFA and CCL19), and 19 cytokines had significantly higher circulating plasma levels prior to FDR adjustment. No cytokine levels were higher among controls. Conclusions and Relevance: In this cohort study of patients with melanoma treated with adjuvant anti-PD-1 therapy, chronic irAEs were common, persistent, and associated with elevated circulating cytokines, suggesting possible candidate inflammatory pathways for future validation. Later irAE onset and corticosteroid-treated irAEs were associated with chronicity of irAEs. Given the long-term survival of these patients, monitoring and managing chronic irAEs is crucial.