Randomized Phase II Trial of Pazopanib Versus Placebo in Patients With Advanced Extrapancreatic Neuroendocrine Tumors (Alliance A021202).

Pazopanib, an oral multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, PDGFR-alpha and-beta, and c-Kit, was tested for efficacy in epNET.

帕唑帕尼是一种口服多靶点激酶抑制剂，对血管内皮生长因子受体（VEGFR）-2和-3、血小板衍生生长因子受体（PDGFR）-alpha和-beta以及c-Kit具有活性，其在epNET中的疗效正在接受测试。

patients_and_methods

We conducted a multicenter, randomized, double-blind, phase II study of pazopanib (800 mg once daily) versus placebo in low- to intermediate-grade epNET with radiologic progressive disease (PD) within 12 months of study entry.

我们开展了一项多中心、随机、双盲、II期研究，对比了每日一次800毫克帕唑帕尼与安慰剂在低至中度分化肠神经内分泌肿瘤（epNET）中的效果，这些肿瘤在研究开始后12个月内出现放射学进展（PD）。

Previous somatostatin analog (SSA) was required for midgut tumors, and concurrent SSA was allowed.

对于中肠肿瘤，之前必须使用生长抑素类似物（SSA），并且允许同时使用SSA。

The primary end point was progression-free survival(PFS) by blinded independent central review.

主要终点是通过盲法独立中央审查的无进展生存期（PFS）。

Unblinding and crossover were allowed if PD was confirmed by central review.

如果中央审查确认疾病进展（PD），则允许揭盲和交叉治疗。

Results

One hundred seventy-one patients (97 pazopanib and 74 placebo) were randomly assigned between September 2013 and October 2015.

2013年9月至2015年10月期间，171名患者（97名接受帕唑帕尼治疗，74名接受安慰剂）被随机分配。

The majority had a midgut primary site (75%) and previous SSA treatment (93%).

大多数患者（75%）的原发部位为中肠，且93%的患者之前接受过生长抑素类似物（SSA）治疗。

About half (49%) of the patients had functional tumors.

大约一半（49%）的患者有功能性肿瘤。

The median follow-up was 61 months (95% CI, 60 to 63).

中位随访时间为61个月（95%置信区间，60至63个月）。

Median PFS was 11.8 versus 7.6 months in pazopanib versus placebo, respectively (hazard ratio, 0.54 [95% CI, 0.37 to 0.79]; P < .001); 49 placebo patients crossed over to pazopanib.

帕唑帕尼与安慰剂的中位无进展生存期分别为11.8个月和7.6个月（风险比，0.54 [95% 置信区间，0.37至0.79]；P < .001）；49名安慰剂患者转用帕唑帕尼。

There was no significant difference in overall survivalbetween the treatment arms.

治疗组之间的总生存期没有显著差异。

Rates of grade 3 or greater adverse events (regardless of attribution) were higher in pazopanib versus placebo (84% v 47%; P < .001), as were grade 5 death events (8% v 0%, P = .017).

与安慰剂相比，帕唑帕尼组3级或更高级别的不良事件（无论归因如何）发生率更高（84%对比47%；P<.001），5级死亡事件的发生率也更高（8%对比0%，P=.017）。

Conclusions

Pazopanib compared with placebo significantly improves PFS in patients with progressive epNET, confirming that the VEGF signaling pathway is a valid target for therapy in epNET.

帕唑帕尼与安慰剂相比，在进展性epNET患者中显著改善了无进展生存期（PFS），证实了VEGF信号通路是epNET治疗的有效靶点。

However, after integrating the associated risks relative to the benefits, further development of pazopanib in this clinical context is not planned.

然而，在综合考虑与益处相关的风险后，目前不计划在这一临床背景下进一步开发帕唑帕尼。