A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial)

Abstract

Background: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO).

Patients and methods: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year.

Results: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9).

Conclusions: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

Keywords: CTLA-4; PD-1; immune checkpoint inhibitor; isolated hepatic perfusion; liver metastases; uveal melanoma.

Figure 1

Study design and CONSORT diagram. (A) Treatment outline and (B) CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; IHP, isolated hepatic perfusion; IPI3/NIVO1, ipilimumab 3 mg/kg and nivolumab 1 mg/kg; NIVO, nivolumab 480 mg fixed dose; mo, months; R, randomization; w, weeks. Created with BioRender.com.

Figure 2

Response, treatment and patient outcomes. (A) Change in target lesion size from baseline. (B) Treatment and response timeline. (C) Progression-free survival. Tick marks indicate censored data. CR, complete response; ICI, immune checkpoint inhibitor; IHP, isolated hepatic perfusion; PD, progressive disease; PR, partial response.