A Pilot Study of Hepatic Irradiation with Yttrium-90 Microspheres Followed by Immunotherapy with Ipilimumab and Nivolumab for Metastatic Uveal Melanoma

Abstract

Background: Liver metastases from uveal melanoma carry a very poor prognosis. Hepatic artery infusions with Yttrium-90 ( 90 Y) resin microspheres have some activity in this disease, and radiation and immunotherapy may be synergistic. The primary objective of this study was to determine the safety and tolerability of sequential 90 Y resin microspheres and immunotherapy with ipilimumab and nivolumab in metastatic uveal melanoma. Materials and Methods: Twenty-six patients with uveal melanoma with hepatic metastases were entered into a pilot study. Treatment consisted of two infusions of 90 Y resin microspheres, one to each lobe of the liver, followed in 2–4 weeks by immunotherapy with ipilimumab and nivolumab every 3 weeks for four doses, then maintenance immunotherapy with nivolumab alone. Results: Initial dosing of both 90 Y and immunotherapy resulted in excessive toxicity. With decreasing the dosage of 90 Y to limit the normal liver dose to 35Gy and lowering the ipilimumab dose to 1 mg/kg, the toxicity was tolerable, with no apparent change in efficacy. There was one complete and four confirmed partial responses, for an objective response rate of 20% and a disease control rate of 68%. The median progression-free survival was 5.5 months (95% confidence interval [CI]: 1.3–9.7 months), with a median overall survival of 15 months (95% CI: 9.7–20.1 months). Conclusions: With dose reductions, sequential therapy with 90 Y and immunotherapy with ipilimumab and nivolumab is safe and tolerable, and has activity in metastatic uveal melanoma. These results justify a controlled trial to demonstrate whether 90 Y resin microspheres add to the utility of combination immunotherapy in this disease. Clinical Trial Registration number: NCT02913417.

The Future of Checkpoint Inhibitors in Uveal Melanoma: A Narrative Review

“…In conclusion, completed clinical trials have demonstrated that both dual-agent ICIs and SIRT plus ICIs are effective, with a manageable toxicity profile, in treating patients with MUM [ 37 , 38 , 60 ]. When the patients' genetic characteristics limit the option of tebentafusp, these two regimens should be considered for patients.…”

“…In a multicenter single-arm phase I/II trial, a 5.5-month median PFS, 15-month median OS, and ORR of 20% were observed in 26 patients with UM with hepatic metastasis involving less than 50% of the liver. These patients were treated with hepatic artery infusions with a relatively low dose of yttrium-90 (Y-90) as well as ipilimumab and nivolumab (35 Gy for Y-90 and 1 mg/kg for ipilimumab) [ 60 ]. Another patient with MUM was even reported to be free of disease for at least 14 months after treatment with SIRT and ipilimumab [ 61 ].…”

Minimally Invasive Treatment Options for Hepatic Uveal Melanoma Metastases

“…It is important to note that the initial dosing of 90Y and ipilimumab resulted in excessive toxicity. However, by limiting the background liver dose to 35 Gy and lowering the ipilimumab dose, toxicity was tolerable, and efficacy was not changed [68]. Radioembolization is felt to enhance the efficacy of immunotherapy by creating an immunogenic environment in the tumor [69].…”

Uveal melanoma: Recent advances in immunotherapy

“…Minor et al [ 40 ] conducted a pilot study on 26 patients with hepatic metastases of UM treated with two cycles of selective internal radiation therapy (SIRT) with yttrium-90 (90Y) resin microspheres, one to each lobe of the liver, followed in 2-4 wk by immunotherapy with ipilimumab/nivolumab every 3 wk for four doses, then maintenance immunotherapy with nivolumab alone. Initial dosing of both 90Y and immunotherapy resulted in excessive toxicity but, after decreasing the dosage of 90Y microspheres to limit the radiation dose to normal liver to 35 Gy and lowering the ipilimumab dose to 1 mg/kg, the treatment was tolerable.…”