■临床前研究表明,精氨酸剥夺在精氨酸琥珀酸合成酶1(ASS1)阴性的癌症中具有合成致死性,包括间皮瘤.在一项随机和生物标志物驱动的癌症患者研究中,尚未评估精氨酸降低剂聚乙二醇化精氨酸脱亚胺酶(ADI-PEG20)的作用。
■评估精氨酸耗竭对ASS1缺陷型恶性胸膜间皮瘤患者的临床影响。
■一项多中心2期随机临床试验,精氨酸脱亚胺酶与间皮瘤(ADAM)研究,在2011年3月2日至2013年5月21日期间,在8个学术癌症中心进行。对201例患者(2011-2013年)进行免疫组织化学筛查,发现68例晚期ASS1缺陷型恶性胸膜间皮瘤。
■随机化2:1精氨酸剥夺(ADI-PEG20,36.8mg/m2,每周肌内注射)加最佳支持治疗(BSC)或单独BSC。
■主要终点是通过改良的实体瘤反应评估标准(RECIST)评估的无进展生存期(PFS)(目标风险比,0.60)。次要终点是总生存期(OS),肿瘤反应率,安全,和生活质量,根据治疗意向进行分析。我们测量了血浆精氨酸和瓜氨酸水平,抗ADI-PEG20抗体滴度,ASS1甲基化状态,和18F-氟代脱氧葡萄糖正电子发射断层扫描的代谢反应。
■68名成年人的中位(范围)随访(中位[范围]年龄,66[48-83]岁;19%为女性)为38(2.5-39)个月。PFS风险比为0.56(95%CI,0.33-0.96),ADI-PEG20组的中位数为3.2个月,BSC组的中位数为2.0个月(P=0.03)(绝对风险,6个月时为18%vs0%)。4个月时的最佳反应(改良的RECIST)是疾病稳定:ADI-PEG20组23个中的12个(52%),BSC组9个中的2个(22%)(P=.23)。OS曲线交叉,因此使用预期寿命:ADI-PEG20组15.7个月vsBSC组12.1个月(差异3.6[95%CI,-1.0~8.1]个月;P=.13).ADI-PEG20组的至少3级症状不良事件发生率为44例(25%)中的11例,而BSC组的24例(17%)中的4例(P=.43),最常见的是免疫相关的,非发热性中性粒细胞减少症,胃肠事件,和疲劳。差异ASS1基因体甲基化与ASS1免疫组织化学相关,更长的精氨酸剥夺与改善的PFS相关。
■在此试验中,ADI-PEG20的精氨酸剥夺可改善ASS1缺陷型间皮瘤患者的PFS。靶向精氨酸是安全的,值得在精氨酸依赖性癌症中进行进一步的临床研究。
■clinicaltrials.gov标识符:NCT01279967。
UNASSIGNED: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven
study among patients with cancer.
UNASSIGNED: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma.
UNASSIGNED: A multicenter phase 2 randomized clinical
trial, the Arginine Deiminase and Mesothelioma (ADAM)
study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma.
UNASSIGNED: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone.
UNASSIGNED: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography.
UNASSIGNED: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS.
UNASSIGNED: In this
trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers.
UNASSIGNED: clinicaltrials.gov Identifier: NCT01279967.