Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments.,Here we genomically profile metastatic tumors and infiltrating lymphocytes.,BAP1 alterations are overrepresented and found in 29/32 of cases.,Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease.,One outlier tumor has a high mutational burden associated with UV-damage.,CDKN2A deletions also occur, which are rarely present in primaries.,A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains.,Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant.,This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.,The genetics of uveal melanoma has mainly been studied in primary tumours.,In this study, the authors perform whole genome sequencing as well as immune cell profiling of biopsy samples obtained from metastatic uveal melanoma patients, providing an updated genomic landscape of these advanced lesions.
Ipilimumab improves survival in patients with advanced melanoma.,The activity and safety of ipilimumab outside of a clinical trial was assessed in an expanded access programme (EAP).,Ipilimumab was available upon physician request for patients aged 16 or over with pretreated stage III (unresectable)/IV melanoma, for whom no other therapeutic option was available.,Patients received ipilimumab 3 mg/kg every 3 weeks for four doses.,Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression.,Tumour assessments were conducted at baseline and week 12.,Patients were monitored for adverse events (AEs) within 3 to 4 days of each scheduled visit.,Of 855 patients participating in the EAP in Italy, 833 were evaluable for response.,Of these, 13% had an objective immune response, and the immune-related disease control rate was 34%.,Median progression-free survival and overall survival were 3.7 and 7.2 months, respectively.,Efficacy was independent of BRAF and NRAS mutational status.,Overall, 33% of patients reported an immune-related AE (irAE).,The frequency of irAEs was not associated with response to ipilimumab.,Outside of a clinical trial setting, ipilimumab is a feasible treatment option in patients with pretreated metastatic melanoma, regardless of BRAF and NRAS mutational status.,Data from this large cohort of patients support clinical trial evidence that ipilimumab can induce durable disease control and long-term survival in patients who have failed to respond to prior treatment.