PURPOSE About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively ( P < .0001). The median PFS was 7.4 months versus 3.3 months ( P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months ( P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

LBA9509 Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of the patients, with the liver being the most common site. The median survival for patients with liver metastases is about 6-12 months, and there are only few systemic treatment options available that moderately prolong survival. A previous trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival, compared with a historical control group consisting of the longest surviving patients in Sweden during the same time period (26 vs. 12 months). Methods: In this multicenter randomized, controlled, phase III trial, patients with previously untreated isolated liver metastasis from uveal melanoma were randomized between 2013 and 2021 to receive IHP or best alternative care (control group). The primary end point is overall survival at 24 months, but here we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS) and toxicity. Results: A total of 93 patients were randomized, with three patients in each group being excluded due to either withdrawal of consent or inappropriate enrollment, and a total of 87 patients were assigned to either IHP group (43 patients) or control group (44 patients). In the IHP group, 41 (89%) patients were treated per protocol, and in the control group, 49% of the patients were treated with chemotherapy, 39% with immunotherapy and 9% with localized treatment interventions. In an intention-to-treat analysis, the overall response rate (ORR) in the IHP group was 40% (17/43) compared to 4.5% (2/44) in the control group (p<0.0001). The median hPFS in the IHP group was 9.1 months (95% CI, 5.6 to 13.4 months), compared to 3.3 months (95% CI, 2.9 to 4.0 months) in the control group (p<0.0001). The median PFS in the IHP group was 7.4 months (95% CI, 5.2 to 11.6 months), compared to 3.3 months (95% CI, 2.9 to 3.7 months) in the control group (p<0.0001). There were 14 treatment-related serious adverse events in the IHP group, where vascular complication and infections were the most common side effects, compared to 13 in the control group where immunotherapy related side effects were most common. There was one treatment related death in the IHP group. Conclusions: Treatment with IHP resulted in superior ORR, hPFS and PFS compared to best alternative care among previously untreated patients with isolated uveal melanoma liver metastasis. Clinical trial information: NCT01785316.

LBA9512 Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of the patients, with the liver being the most common site. The median survival for patients with liver metastases is about 6-12 months, and there are only few systemic treatment options available providing only small survival benefits. The SCANDIUM trial previously demonstrated significantly superior response rate (40% vs 4.5%) and progression free survival (7.4 vs 3.3 months), compared to best alternative care, in patients with liver metastases of uveal melanoma receiving first-line treatment with isolated hepatic perfusion (IHP). Here we present the primary endpoint, overall survival (OS) rate at 24 months. Methods: In this multicenter randomized, controlled, phase III trial, adult patients with a performance status ECOG 0-1, and with previously untreated isolated liver metastasis from uveal melanoma, were randomized 1:1 between 2013 and 2021 to receive a one-time treatment with IHP or best alternative care (control group). No crossover from the control group to the IHP group was allowed. The primary endpoint was OS rate at 24 months, with the hypothesis of a treatment effect leading to a 50% OS rate in the IHP group compared to 20% in the control group. Results: A total of 93 patients were randomized, with three patients in each group being excluded due to either withdrawal of consent or inappropriate enrollment, and a total of 87 patients were assigned to either IHP group (43 patients) or control group (44 patients). In the IHP group, 41 (89%) patients received IHP. In the control group, the first-line of treatment was chemotherapy (49%), immunotherapy (39%) or localized treatment interventions (9%). In the intention-to-treat (ITT) population, the OS rate at 24 months in the IHP group was 46.5% (95% CI, 31.2-60.4%) compared to 29.5% (95% CI, 17.0-43.2%) in the control group (p = 0.12, Fisher’s exact test). The median OS in the IHP group was 21.7 months (95% CI, 19.1-NA months) compared to 17.6 months (95% CI, 13.5-21.4 months) in the control group (p = 0.10, log-rank test), with a hazard ratio of 0.64 (95% CI 0.37-1.10) in favor of the IHP group. Conclusions: In the SCANDIUM trial, patients with metastatic uveal melanoma receiving IHP experienced a significantly improved PFS. At two years, OS was longer in patients receiving IHP, but the difference was not statistically significant. This could in part be attributed to the control group performing better than expected, potentially due to the introduction of immunotherapy during the study period. Prolonged follow-up of the cohorts will further elucidate how IHP affects OS in patients with uveal melanoma. Clinical trial information: NCT01785316 .

9533 Background: Uveal melanoma is a rare disease characterized by liver metastasis and a very poor prognosis. In patients with metastatic UM, a single 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) every third week (IPI3/NIVO1 q3w) for four cycles followed by nivolumab monotherapy has shown response rates of 11-18%. The impact of these treatments on overall survival, especially if combined, is unclear. This phase I trial investigates the safety and tolerability of the combination of IHP and IPI3/NIVO1. Methods: Eligible in this multicenter open, randomized, controlled, phase I trial, were patients with liver dominant metastatic uveal melanoma who had not received previous systemic treatment. Patients were randomized to receive either (Arm A) IHP followed by combination immunotherapy (four cycles IPI3/NIVO1 q3w) or (Arm B) one neoadjuvant cycle of IPI3/NIVO1 prior to IHP followed by three cycles IPI3/NIVO1 q3w. Thereafter, both Arm A and B received monotherapy with nivolumab (480 mg q4w) for up to 1 year. IHP 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 while, secondary endpoints included response according to RECIST v1.1 criteria reported according by the local investigator. Results: A total of 18 patients were included and randomized, nine to Arm A and nine to Arm B. Three patients did not undergo IHP as planned, one due to perioperative complications (Arm A), one due to extensive metastatic liver infiltration ( > 50% liver volume) (Arm B) and one due to encephalitis related to neoadjuvant IPI3/NIVO1 (Arm B). A total of 20 serious adverse events (SAEs) were reported in eleven patients. There were ten SAEs in each arm, with no treatment related deaths. In total, 11 of 18 patients (six in Arm A and five in arm B) did not complete the planned four cycles of IPI3/NIVO1, with a mean of 2.4 cycles in Arm A and 3.0 cycles in Arm B. Response was evaluable in 17 patients, with the best clinical responses reported as three complete responses (18%), four partial responses (24%), seven stable disease (41%) and three progressive disease (18%). The overall response rate was 63% in Arm A (5/8) and 22% in Arm B (2/9). Conclusions: For previously untreated patients with liver dominant metastatic uveal melanoma, treatment with IHP in combination with IPI3/NIVO1 had a high, yet manageable toxicity profile. The efficacy of this combination treatment is encouraging, however, one cycle of neoadjuvant IPI3/NIVO1 given before IHP did not seem beneficial, neither in regards to safety nor efficacy. Clinical trial information: NCT04463368 .