Chronic Immune-Related Adverse Events Persist in Melanoma Patients Receiving Adjuvant Anti–PD-1 Therapy: JAMA
USA: Chronic immune-related adverse events (irAEs) were common and persistent among patients with melanoma treated with adjuvant anti–PD-1 therapy, with many events continuing despite prolonged follow-up, a cohort study published in JAMA Network Open has shown.
The findings highlight the need for long-term monitoring of immune checkpoint inhibitor (ICI)-related toxicities as these treatments improve survival among patients with high-risk resected melanoma. Later onset of irAEs and corticosteroid treatment were associated with chronicity, while elevated circulating cytokines pointed to potential inflammatory pathways.
Researchers led by Roma A. Kankaria from the Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, and colleagues conducted a retrospective cohort study across seven institutions in the United States and Australia. The study included patients with stage III to IV melanoma who received adjuvant anti–PD-1 therapy between 2015 and 2024 and had at least 12 months of follow-up after treatment discontinuation.
The analysis assessed the incidence and characteristics of chronic irAEs, defined as toxicities persisting for at least three months after anti–PD-1 therapy ended. Researchers also examined demographic and treatment-related factors associated with chronicity and evaluated circulating cytokine levels.
Among 303 patients, with a median age of 64 years and 61% men, 220 (73%) developed acute irAEs and 146 (48%) experienced chronic irAEs. The most frequent chronic toxicities were hypothyroidism, arthritis, and dermatitis. At the final follow-up, 102 patients (34%) continued to have chronic irAEs.
Key findings included:
- Chronic irAEs developed later than nonchronic events, with a median onset of 153 days versus 99 days.
- Corticosteroid exposure was more frequent among chronic irAEs than nonchronic events.
- Among 300 nonendocrine irAE events, corticosteroid-treated patients with earlier-onset irAEs had higher odds of chronic toxicity.
- Eight cytokines, including VEGFA and CCL19, remained significantly elevated among patients with chronic irAEs after false discovery rate adjustment.
- Nineteen cytokines showed higher circulating levels before adjustment, suggesting several potential inflammatory pathways for further investigation.
The researchers noted that electronic medical record data may not capture treatment-related toxicities as precisely as formal clinical trial reporting. The observational design also prevents establishing causal relationships between corticosteroid treatment, timing of irAEs, and chronicity. In addition, patients with shorter survival, including those who died early from cancer progression, were not captured.
Overall, chronic irAEs were frequent and often persistent among melanoma patients receiving adjuvant anti–PD-1 therapy. The findings suggest that later irAE onset and corticosteroid treatment may help identify patients at greater risk of prolonged toxicity, while elevated cytokines may provide clues to underlying inflammatory mechanisms. Further research is needed to validate these biomarkers and develop strategies for preventing and managing chronic ICI-related toxicities.
Reference:
Kankaria RA, Fankhauser R, Boutros A, et al. Anti–PD-1 Therapy and Long-Term Toxic Effects Among Patients With Melanoma. JAMA Netw Open. 2026;9(10):e2637199. doi:10.1001/jamanetworkopen.2026.37199
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