Uveal melanoma (UM) is an uncommon malignancy (0.6-0.7 cases/100.000/year) that, in the case of metastatic stage, has a poor prognosis for response to treatment and survival. It is remarkable for its purely hematogenous pattern of dissemination, most commonly to the liver (60%) and lungs (25%). Current approaches using percutaneous hepatic perfusion (PHP) with melphalan resulted in response rates of up to 40% in the liver (1, 2) (for results of our own phase II study see paragraph 6.3.2). However, a main part of the patients developed extrahepatic disease in the follow-up, whereas the liver metastases were mainly stable.

Checkpoint inhibitors have been shown to improve overall survival in metastasized cutaneous melanoma in phase III studies (3-6), but seem to have limited activity as monotherapies in metastasized uveal melanoma (7-9). The combination of ipilimumab and nivolumab has achieved 2 out of 6 patients PR in a retrospective analysis (10). Interestingly, both patients had a liver-directed therapy (SIRT and chemoembolization) before the immunotherapy.

Combination of radio-frequency ablation (RFA) and anti-CTLA-4 enhanced antigen-loading of dendritic cells, and induced long-lasting anti-tumor immune responses in a murine melanoma model without induction of any severe side effects (11, 12). A phase Ib/II trial by Blank et al. (13) showed unconfirmed responses in some patients when RFA was combined with ipilimumab in uveal melanoma, but long-term disease stabilization was not achieved. Most of the responses were seen in extrahepatic metastases. Combining percutaneous hepatic perfusion (PHP) with checkpoint inhibitors could together lead to control of hepatic and extrahepatic disease. Therefore, we propose the current trial: Phase1b/2 Study Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced Uveal Melanoma (CHOPIN).