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

Purpose. To assess neurocognitive function (NCF), psychosocial outcome, health-related quality of life (HRQoL), and long-term effects of immune-related adverse events (irAE) on metastatic melanoma survivors treated with ipilimumab (IPI). Methods. Melanoma survivors were identified within two study populations (N=104), at a single-center university hospital, and defined as patients who were disease-free for at least 2 years after initiating IPI. Data were collected using 4 patient-reported outcome measures, computerized NCF testing, and a semistructured interview at the start and 1-year follow-up. Results. Out of 18 eligible survivors, 17 were recruited (5F/12M); median age is 57 years (range 33-86); and median time since initiating IPI was 5.6 years (range 2.1-9.3). The clinical interview revealed that survivors suffered from cancer-related emotional distress such as fear of recurrence (N=8), existential problems (N=2), survivor guilt (N=2), and posttraumatic stress disorder (N=6). The mean EORTC QLQ-C30 Global Score was not significantly different from the European mean of the healthy population. Nine survivors reported anxiety and/or depression (Hospitalization Depression Scale) during the survey. Seven survivors (41%) reported fatigue (Fatigue Severity Scale). Seven patients (41%) had impairment in NCF; only three out of seven survivors had impairment in subjective cognition (Cognitive Failure Questionnaire). Anxiety, depression, fatigue, and neurocognitive symptoms remained stable at the 1-year follow-up. All cases of skin toxicity (N=8), hepatitis (N=1), colitis (N=3), and sarcoidosis (N=1) resolved without impact on HRQoL. Three survivors experienced hypophysitis; all suffered from persistent fatigue and cognitive complaints 5 years after onset. One survivor who experienced a Guillain-Barré-like syndrome suffered from persisting depression, fatigue, and impairment in NCF. Conclusion. A majority of melanoma survivors treated with IPI continue to suffer from emotional distress and impairment in NCF. Timely detection in order to offer tailored care is imperative, with special attention for survivors with a history of neuroendocrine or neurological irAE. The trial is registered with B.U.N. 143201421920.

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.

Immune checkpoint inhibitors (ICI) and targeted therapies form the therapeutic mainstay for v-Raf murine sarcoma viral oncogene homolog B V600-mutated metastatic melanoma. Both treatment regimens can cause inflammatory arthritis. The reported incidence of treatment-induced inflammatory arthritis is low, though presumably underestimated due to lack of awareness, clear definitions and uniform grading systems. Nevertheless, recognition is important as inflammatory arthritis can become chronic and thus affect the quality of life beyond treatment. In this short communication, we present two patients with metastatic melanoma treated with ICI and targeted therapies who develop severe polyarthritis. Based on their clinical discourse we describe standard inflammatory arthritis treatment modalities and more advanced immunomodulatory treatment options with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologic DMARDs (bDMARDs). Long-term immunosuppressive treatment with glucocorticoids or DMARDs in this setting raises concerns about antitumour response and potential carcinogenic risk. Current literature on this topic is scarce, heterogeneous and retrospective. Prospective analysis of cancer patients treated with DMARDs is needed to clearly address these concerns.