Bergsland Emily K, Geyer Susan, Asmis Timothy R, Behr Spencer C, Kuebler J Philip, Kumthekar Priya, Mazza Gina, Maitland Michael L, Niedzwiecki Donna, Nixon Andrew B, Schwartz Lawrence Howard, Strosberg Jonathan R, Venook Alan P, O'Reilly Eileen M, Meyerhardt Jeffrey A
Department of Medicine, University of California San Francisco, San Francisco, CA.
Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN.
J Clin Oncol. 2025 Oct 10;43(29):3170-3183. doi: 10.1200/JCO-24-02644. Epub 2025 Sep 3.
Patients with advanced, well-differentiated extrapancreatic neuroendocrine tumors (epNETs) have limited systemic treatment options. 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.
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. Previous somatostatin analog (SSA) was required for midgut tumors, and concurrent SSA was allowed. The primary end point was progression-free survival (PFS) by blinded independent central review. Unblinding and crossover were allowed if PD was confirmed by central review.
One hundred seventy-one patients (97 pazopanib and 74 placebo) were randomly assigned between September 2013 and October 2015. The majority had a midgut primary site (75%) and previous SSA treatment (93%). About half (49%) of the patients had functional tumors. The median follow-up was 61 months (95% CI, 60 to 63). 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]; < .001); 49 placebo patients crossed over to pazopanib. There was no significant difference in overall survival between the treatment arms. Rates of grade 3 or greater adverse events (regardless of attribution) were higher in pazopanib versus placebo (84% 47%; < .001), as were grade 5 death events (8% 0%, = .017).
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. However, after integrating the associated risks relative to the benefits, further development of pazopanib in this clinical context is not planned.
晚期高分化胰腺外神经内分泌肿瘤（epNETs）患者的全身治疗选择有限。帕唑帕尼是一种口服多激酶抑制剂，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）-α和-β以及c-Kit具有活性，本研究对其在epNET中的疗效进行了测试。
我们进行了一项多中心、随机、双盲、II期研究，比较帕唑帕尼（每日一次，800 mg）与安慰剂在低至中级epNET患者中的疗效，这些患者在研究入组后12个月内出现影像学进展性疾病（PD）。中肠肿瘤患者需要先前使用过生长抑素类似物（SSA），允许同时使用SSA。主要终点是通过盲法独立中央审查得出的无进展生存期（PFS）。如果中央审查确认出现PD，则允许揭盲和交叉治疗。
2013年9月至2015年10月期间，共随机分配了171例患者（97例接受帕唑帕尼治疗，74例接受安慰剂治疗）。大多数患者的原发部位在中肠（75%），并且先前接受过SSA治疗（93%）。约一半（49%）的患者患有功能性肿瘤。中位随访时间为61个月（95%CI，60至63个月）。帕唑帕尼组和安慰剂组的中位PFS分别为11.8个月和7.6个月（风险比，0.54 [95%CI，0.37至0.79]；P <.001）；49例接受安慰剂治疗的患者交叉接受了帕唑帕尼治疗。治疗组之间的总生存期无显著差异。帕唑帕尼组3级或更高级别不良事件（无论归因如何）的发生率高于安慰剂组（84%对47%；P <.001），5级死亡事件的发生率也是如此（8%对0%，P =.017）。
与安慰剂相比，帕唑帕尼显著改善了进展期epNET患者的PFS，证实VEGF信号通路是epNET治疗的有效靶点。然而，综合相关风险与益处后，目前不计划在该临床背景下进一步开发帕唑帕尼。
