Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma
Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma
复制标题
DOI：
10.1093/annonc/mdy101
复制
发表时间：
2018-06-01
影响因子：
50.5
通讯作者：
Chen, L-T.
中科院分区：
文献类型：
--
作者：
Abou-Alfa, G. K.;Qin, S.;Chen, L-T.
背景精氨酸耗竭是肝细胞癌（HCC）的一个假定靶点。HCC通常缺乏谷氨酰琥珀酸合成酶，一种瓜氨酸到谷氨酰胺的补充酶。ADI-PEG 20是一种克隆的精氨酸降解酶，精氨酸脱亚胺酶与聚乙二醇偶联。本研究的目的是评估这种药物作为一种潜在的新的治疗HCC一线系统therapeutic.Methods和patientsPatients组织学证实的晚期HCC和Child-Pugh高达B7与以前的系统治疗，随机2：1 ADI-PEG 20 18 mg/m2与安慰剂肌肉注射每周。主要终点是总生存期（OS），有93%的把握度检测到中位OS延长45.6个月（单侧a = 0.025）。次要终点包括无进展生存率，安全性和精氨酸correlators.ResultsA共635例患者入组：中位年龄61，82%男性，60%亚洲，52%肝炎B，26%丙型肝炎，76% IV期，91% Child-Pugh A，70%索拉非尼B和16%进展不耐受。ADI-PEG 20的中位OS为7.8个月，安慰剂为7.4个月（P = 0.88，HR = 1.02），中位无进展生存期为2.6个月，安慰剂为2.6个月（P = 0.07，HR = 1.17）。≥ 3级速发过敏反应发生3级疲乏和食欲减退。治疗结束后30天内的死亡率，ADI-PEG 20组为15.2%，安慰剂组为10.4%，与治疗无关。事后分析精氨酸评估在4，8，12和16周，表现出改善OS的趋势，为那些更长的精氨酸depletion.ConclusionADI-PEG 20单药治疗没有表现出OS的好处，在第二行设置为HCC。耐受性良好。增强长期精氨酸消耗和协同ADI-PEG 20作用的策略正在进行中。
BackgroundArginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzymearginine deiminaseconjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy.Methods and patientsPatients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 45.6 months increase in median OS (one-sided a = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives.ResultsA total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in = grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion.ConclusionADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway.