Overall survival after isolated hepatic perfusion in combination with ipilimumab and nivolumab in patients with uveal melanoma metastases (the SCANDIUM II trial).
Authors: Nelson Axel , Shafazand Amir , Cahlin Christian , Carneiro Ana , Helgadottir Hildur , Levin Max , Rizell Magnus , Ullenhag Gustav J. , Wirén Sara , Lindner Per , Nilsson Jonas A , Ny Lars , Olofsson Bagge Roger 
Published: July 2024

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Background: Uveal melanoma (UM) is a rare disease, that commonly metastases to the liver metastases and has a very poor prognosis. In patients with metastatic UM to the liver, a one-time treatment with isolated hepatic perfusion (IHP) with high dose melphalan has shown response rates of 40%, while immune checkpoint blockade with ipilimumab (3 mg/kg) in combination with nivolumab (1 mg/kg) (IPI3/NIVO1) has shown response rates of 11-18%. The impact of these treatments on overall survival (OS), if combined, is unclear. In the SCANDIUM II trial, we investigated the safety and tolerability of combination of IHP and IPI3/NIVO1. Methods: In this multicenter open, randomized, controlled, phase Ib trial, patients with liver dominant metastatic uveal melanoma were randomized to receive either IHP followed by combination immunotherapy (four cycles IPI3/NIVO1) (Arm A) or one cycle of IPI3/NIVO1 before IHP followed by three cycles IPI3/NIVO1 (Arm B). Thereafter, patients in both Arm A and B received monotherapy with nivolumab (480 mg q4w) for up to 1 year. Isolated hepatic perfusion was performed using melphalan 1mg/kg perfused through the liver for 60 minutes under hyperthermia (40°C). The primary endpoint was incidence and severity of adverse events. Results: In total, 18 patients were included in the trial, 9 randomized to Arm A and 9 to Arm B. 78% were treatment naïve; 28% had both hepatic and extra-hepatic metastases. Three patients did not undergo IHP as planned, one in arm A and two in arm B. Patients received a mean of 2.4 cycles of IPI/NIVO in Arm A and 3.0 cycles in Arm B. There were more IPI/NIVO related adverse events (grade I-IV) in arm B (48 vs. 86). The overall response rate was 38%, 57% in arm A and 22% in arm B, and the median duration of response was 11.9 months (95% CI, 8.2-NE, n = 6). At a minimum follow-up of 18 months, the overall survival rate was 50% (95% CI, 31.5-79.4%) in the whole study population, 56% (95% CI, 31-99%) in arm A and 44% (95% CI, 21-92%) in arm B. The median OS in arm A was 18.2 months (95% CI, 13.2-NA months) and 17.2 months (95% CI, 14.0-NA months) in arm B. The primary endpoint of adverse events has been reported previously. Conclusions: In patients with liver dominant metastatic uveal melanoma, combining IHP with IPI3/NIVO1 is a feasible treatment. One dose of IPI3/NIVO1 before IHP had no obvious benefit in response or OS, but was associated with higher rates of toxicity. There was no apparent survival advantage compared to patients in the SCANDIUM trial with IHP only, however, sample size and non-overlapping patient characteristics severely hamper comparison between the trials. The numerically higher response rate in Arm A warrants a larger randomized study that is designed to detect a difference between IPI/NIVO with or without IHP. Clinical trial information: NCT01785316 .