Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages.,The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.,Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers.,Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety.,Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.,The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively.,The median duration of response was 25.5 months (range 9.0-65.0).,Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0).,The median PFS was 3.0 months (95% CI 2.4-3.6).,The median OS was estimated to 16.1 months (95% CI 12.9-19.3).,Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%).,The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%).,A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).,The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma.,This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
The absence of BRCA1-associated protein 1 (BAP1) expression in uveal melanoma (UM) is associated with metastatic progression and reduced survival.,In this study, we examine nuclear BAP1 (nBAP1) protein expression in primary UMs (PUMs) that show both ‘typical' and ‘atypical' clinical courses according to their chromosome 3 status, and secondary hepatic metastatic UM (MUM), correlating the results with histological, clinical and survival data.,Nuclear BAP1 expression was immunohistochemically assessed in tissue microarrays (TMAs) of: (a) 68 PUM patients, who had been treated surgically; and (b) 13 MUM patients, with 5 cases being paired with primary tumour tissue.,All cases were fully annotated.,The percentage of tumour cell nuclei staining positively for BAP1 was scored by independent observers.,Nuclear BAP1 protein expression was absent in 35 out of 68 (51%) PUM patients, correlating strongly with poor prognostic clinicopathological and genetic parameters and reduced survival (Log rank, P<0.001).,Lack of nBAP1 expression importantly identified a subset of ‘atypical' PUM patients with disomy of chromosome 3 but with unexpected metastatic relapse.,Nuclear BAP1 expression was absent in 10 out of 13 (77%) MUM and expression was concordant in all paired PUM and MUM patients.,Absent nBAP1 protein expression is an independent survival predictor for UM patients, easily examined using immunohistochemistry.