Characteristics and predictors of chronic immune-related adverse events (irAEs) following anti-PD-1 (PD1) treatment for melanoma.

9528 Background: Adjuvant PD1 treatment improves clinical outcomes in high-risk resected melanoma. We have shown that adjuvant PD1 can lead to irAEs that become chronic in up to 46% of treated patients (pts). We performed longer follow-up (f/u) to further characterize chronic irAEs from adjuvant PD1 treatment and assessed risk factors to determine predictors for their development. Methods: We retrospectively analyzed pts treated with adjuvant PD1 for resected stage III-IV melanoma from 2015-2024 from 6 institutions. All pts had at least 12 months of f/u after PD1 initiation. We collected demographics, treatment details, and outcomes. We characterized type, grade, management, duration, and resolution of acute (onset during PD1) and chronic (persisting at least 3 months after PD1 cessation) irAEs. We performed Olink 96-protein inflammation assay in plasma from pts with and without chronic non-endocrine irAEs at 12 months after PD1 initiation. Results: We included 304 pts; 184 (61%) were male, and median age at PD1 initiation was 64 years. Among all pts, 221 (73%) developed acute irAEs, and 147 (48%) developed chronic irAEs; 59 pts had chronic endocrine irAEs, 99 had chronic non-endocrine irAEs, and 11 had both. At last f/u (median 61.4 months), 104 (34%) pts had ongoing irAEs. The most common chronic irAEs were hypothyroidism/thyroiditis (n=45, 15%), arthritis (n=25, 8%), dermatitis (n=17, 6%), hypophysitis/adrenal insufficiency (n=16, 5%), and xerostomia (n=10, 3%). Twenty (7%) pts experienced chronic toxicities outside of classical irAEs, most often fatigue (n=14, 5%), orthostasis (n=2, 1%), and headache (n=2, 1%). We then assessed risk factors for chronic irAEs compared with acute, resolving irAEs (excluding endocrine irAEs since nearly all become chronic). We found that peak steroid dose was similar in patients with and without chronic irAEs (median 50 mg for both groups, p=0.33). Time to irAE onset was similar in patients with and without chronic irAEs (median 91 vs. 114 days, p=0.78). Time to steroids from symptom onset trended longer for those with chronic irAEs (median 7 vs. 4 days, p=0.18) but was not statistically significant. In proteomic analysis, 24/96 cytokines had higher expression (0 with lower expression) in pts with chronic irAE (n=17) compared with controls (n=10), including IL-8 (p=0.02), IL-17 (p=0.049), TNF (p=0.02), VEGFA (p=0.005), and soluble PD-L1 (p=0.03). Conclusions: Among this large cohort of pts with melanoma treated with adjuvant PD1, chronic irAEs were common, persistent, and associated with elevated circulating cytokines, which could suggest possible therapeutics. No obvious predictors of chronic irAEs were identified outside of organ affected; analyses are ongoing. Given the long-term survival of pts treated with adjuvant PD1, monitoring and managing chronic irAEs is crucial.