Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

SIMPLE SUMMARY: Uveal melanoma is a rare subtype of malignant melanoma. It is known to rapidly metastasize, with the liver being the most frequently affected organ. Due to differences from melanoma arising in the skin, such as a lower number of mutations, it responds poorly to immune checkpoint blockade, a treatment approach reinvigorating the patient’s immune system to eliminate the cancer. We here investigated the safety and tolerability of a new combination treatment consisting of two established immunotherapy medications (ipilimumab and nivolumab) with the addition of an experimental arginine depleting medication, pegylated arginine deiminase (ADI-PEG 20), which is thought to make uveal melanoma more amenable to immunotherapy. This novel treatment approach was found to be safe and well-tolerated but did not improve the clinical outcome beyond the expected limited efficacy of approved immunotherapy alone. ABSTRACT: Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.