ASCO 2016:Evofosfamide+吉西他滨改善晚期胰腺癌PFS和ORR

2016-06-07 佚名 医脉通

2016年6月3-7日,一年一度的美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)年会在芝加哥举办。6月6日上午的消化系统(非结直肠)肿瘤口头报告专场上,一项摘要号为4007的随机双盲III期MAESTRO试验,在之前未接受治疗的转移性或局部晚期不可切除的胰腺导管腺癌(PDAC)患者中将evofosfamide(Evo)联合吉西他滨(Ge

2016年6月3-7日,一年一度的美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)年会在芝加哥举办。6月6日上午的消化系统(非结直肠)肿瘤口头报告专场上,一项摘要号为4007的随机双盲III期MAESTRO试验,在之前未接受治疗的转移性或局部晚期不可切除的胰腺导管腺癌(PDAC)患者中将evofosfamide(Evo)联合吉西他滨(Gem)进行研究,整理如下:


胰腺导管腺癌(PDAC)组织缺氧会带来疾病进展和较差预后。Evofosfamide(Evo)是一种Br-IPM缺氧-活化前药,在缺氧条件下优先激活。在一项晚期PDAC的随机II期试验中,Evo加入Gem会显著改善PFS(NCT01144455)。


MAESTRO是一项国际,随机,双盲,安慰剂-对照III期试验,该试验在局部晚期不可切除或转移性PDAC患者中将Evo/Gem与安慰剂(Pbo)/Gem进行比较(NCT01746979)。Evo 340mg/m2或者相匹配的Pbo和Gem 1000mg/m2在第1,8和15天IV给药,28天一个周期。关键合格标准包括ECOG PS 0/1。主要终点是总生存期(OS)。660例患者按照1:1随机分配,获得了508例事件(死亡)以保证90%P值来检出OS的0.75风险比(HR),双侧α为0.05。次要终点包括PFS和客观缓解率(ORR)。


2013年1月到2014年11月,693例患者被随机分配(346例Evo/Gem,347例Pbo/Gem)。基线特征均衡。中位OS分别为:Evo/Gem组8.7个月,Pbo/Gem组7.6个月;HR=0.84(95% CI:0.71-1.01,P=0.059)。中位PFS分别为:Evo/Gem组5.5个月,Pbo/Gem组3.7个月;HR=0.77(95% CI:0.65-0.92,P=0.004)。Evo/Gem组最佳ORR是20%,Pbo/Gem最佳ORR是16%;比值比(OR)=1.32(95% CI:0.88-1.97,P=0.17)。Evo/Gem组经证实的ORR是15%,Pbo/Gem组经证实的ORR是9%;OR=1.90(95% CI:1.16-3.12,P=0.009)。


最常见的非血液学AEs在各组相似:恶心(47%),食欲下降(35%)和呕吐(33%)。血液学AEs包括中性粒细胞减少,血小板减少和贫血,在Evo/Gem组较为常见。AEs导致的死亡在Evo/Gem组有9%,Pbo/Gem组有11%发生。AEs导致的治疗停止在17.9%接受Evo/Gem治疗的患者和15.6%接受Pbo/Gem治疗的患者中发生。


该项试验主要终点未满足OS的时间差异,不具有统计学显著性。Evo/Gem组显示抗肿瘤活性迹象,出现较长的PFS和较高的ORR。安全性与之前报道的类似。临床试验信息:NCT01746979。




原文摘要:


MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).(Abstract4007)


Authors:Eric Van Cutsem, Heinz-Josef Lenz,et al.


Session Type:Oral Abstract Session


Background: Hypoxia in PDAC is associated with disease progression and poor prognosis. Evo is a hypoxia-activated prodrug of Br-IPM that is preferentially activated under hypoxic conditions. The addition of Evo to Gem significantly improved PFS in a randomized phase II trial in advanced PDAC (NCT01144455). 


Methods: MAESTRO was an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo (Pbo)/Gem in pts with locally advanced unresectable or metastatic PDAC (NCT01746979). Evo 340 mg/m2 or matched Pbo and Gem 1,000 mg/m2 were administered IV on days 1, 8, and 15 of a 28-day cycle. Key eligibility criteria included ECOG PS 0/1. The primary endpoint was overall survival (OS). 660 patients were to be randomized 1:1 to obtain 508 events (deaths) to assure 90% power to detect a hazard ratio (HR) of 0.75 for OS with a two-sided α of 0.05. Secondary endpoints included PFS and objective response rate (ORR). 


Results: From Jan 2013 to Nov 2014, 693 pts were randomized (346 Evo/Gem, 347 Pbo/Gem). Baseline characteristics were balanced. Median OS was 8.7 mo with Evo/Gem vs 7.6 mo with Pbo/Gem; HR = 0.84 (95% CI: 0.71–1.01, p = 0.059). Median PFS was 5.5 mo with Evo/Gem vs 3.7 mo with Pbo/Gem; HR = 0.77 (95% CI: 0.65–0.92, p = 0.004). Best ORR was 20% with Evo/Gem vs 16% with Pbo/Gem; odds ratio (OR) = 1.32 (95% CI: 0.88–1.97, p = 0.17). Confirmed ORR was 15% with Evo/Gem vs 9% with Pbo/Gem; OR = 1.90 (95% CI: 1.16 – 3.12, p = 0.009). Most common non-hematologic AEs of nausea (47%), decreased appetite (35%) and vomiting (33%) were similar across arms. Hematologic AEs of neutropenia, thrombocytopenia and anemia were more frequent with Evo/Gem. AEs leading to death were 9% with Evo/Gem vs 11% with Pbo/Gem. AEs leading to treatment discontinuation were 17.9% on Evo/Gem and 15.6% on Pbo/Gem. 


Conclusions: The primary endpoint was not met as difference in OS time was not statistically significant. Evo/Gem showed signs of antitumor activity with longer PFS and higher ORR. The safety profile was similar to that previously reported. Clinical trial information: NCT01746979


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