Abstract：
Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2 ) and Cis (75 mg/m2 ) every 3 weeks plus weekly intramuscular ADI (36 mg/m2 ), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1-deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression-free survival of 3.0 months (range, 1.3-8.1) and a median overall survival of 11.5 months (range, 3.2-36.9). Despite anti-ADI-PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re-expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti-metabolite strategies.
摘要：
转移性葡萄膜黑色素瘤（UM）是一种破坏性疾病，治疗选择很少。我们评估了安全性，在一项针对精氨酸琥珀酸合成酶（ASS1）缺陷的转移性UM患者的1期剂量扩展研究中，使用聚乙二醇化精氨酸脱亚胺酶（ADI-PEG20；聚乙二醇化亚胺酶）联合培美曲塞（Pem）和顺铂（Cis）化疗对精氨酸消耗的耐受性和初步活性。符合条件的患者每3周接受多达6个周期的Pem（500mg/m2）和Cis（75mg/m2），每周肌内ADI（36mg/m2），然后维持ADI直至进展（NCT02029690）。14例患有UM肝转移的ASS1缺陷患者中，有10例接受了ADIPemCis。仅报告1例≥3级发热性中性粒细胞减少不良事件。7例患者病情稳定，中位无进展生存期为3.0个月（范围，1.3-8.1）和中位总生存期11.5个月（范围，3.2-36.9)。尽管出现了抗ADI-PEG20抗体，血浆精氨酸浓度在18周时仍被抑制,血浆瓜氨酸浓度呈倒数升高.进展时的肿瘤再活检显示ASS1再表达是一种逃避机制。在转移性UM中，ADIPemCis的耐受性良好，疾病稳定适度。在UM中表明了精氨酸剥夺的进一步研究，包括与免疫检查点阻断和其他抗代谢物策略的组合。
