The objective of this study was to evaluate the utility of serum C-reactive protein (CRP) as biomarker for the early diagnosis of immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitors (ICIs) in the adjuvant setting, and its potential correlation with relapse-free survival (RFS). Prospectively collected data from 72 melanoma patients treated with adjuvant ICIs were pooled. CRP values at diagnosis of 10 irAEs were descriptively analysed. Correlations between RFS and the occurrence of irAEs, the grade of the irAE, the extent of CRP-elevation and the use of corticosteroids for irAE treatment were investigated. A total of 191 irAEs (grade 1/2, n = 182; grade 3/4, n = 9) occurred in 64 patients [skin toxicity (n = 70), fatigue (n = 50), thyroiditis (n = 12), musculoskeletal toxicity (n = 11), sicca syndrome (n = 10), other (n = 23), pneumonitis (n = 6), colitis (n = 4), hepatitis (n = 3) and hypophysitis (n = 2)]. In pneumonitis and hypophysitis, the median CRP levels at diagnosis exceeded the upper limit of normal (ULN, 5 mg/L). After a median follow-up of 26.5 months, 28 patients (39%) had been diagnosed with a melanoma relapse. Patients who experienced no irAE were at the highest risk for relapse (P = 0.008). A trend was observed for patients diagnosed with an irAE that was associated with an elevated CRP (>2xULN) to be at higher risk for relapse as compared to those diagnosed with an irAE and CRP

Background: Inherited pathogenic variants (PV) in the CDKN2A tumour suppressor gene are among the strongest known risk factors for cutaneous melanoma. CDKN2A encodes for the cell cycle inhibitors p16 ink4 and p14ARF, and dysregulation of the p16/RB1 pathway is a well-known mechanism of resistance to MAPK-directed targeted therapy due to the interplay between the two pathways. For this reason, we wondered whether patients with germline CDKN2A PVs may achieve suboptimal results with BRAF and MEK inhibitors.Methods: We identified twenty CDKN2A PVs carriers who received first-line treatment with BRAF and MEK inhibitors for BRAF-mutant advanced melanoma by reviewing medical records of carriers enrolled in follow-up studies for familial melanoma. By a binomial test, we evaluated if there was a statistically significant difference in the response rate observed in the carriers compared with an expected rate calculated from phase III clinical trials and "real-world" studies. Results:The baseline prognostic features of the 20 identified patients were poorer than those reported in phase III clinical trials, with 12 patients (60%) having stage M1c disease and 5 patients (25%) brain metastases at baseline. Seventeen patients (85%) achieved a partial response; no complete responses were observed. The overall response rate was numerically higher than that expected from phase III trials (66%), although not statistically significant (p-value¼0.097; 95% CI: 0.62-0.97); the difference was statistically significant (p-value¼0.012; 95% CI: 0.62-0.97) when the comparison was performed with real-world studies. Conclusions:The clinical activity of BRAF and MEK inhibitors in patients with BRAFmutant advanced melanoma and germline CDKN2A PVs was not inferior to that observed in clinical trials and real-world studies, which we believe is helpful information for clinicians who manage patients with melanoma.Legal entity responsible for the study: The authors.