BACKGROUND Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti-angiogenic response.

中文翻译：

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[18F] Fluciclatide PET作为铂耐药/难治性卵巢癌对帕唑帕尼和紫杉醇联合治疗反应的生物标志物。

背景技术血管生成是卵巢癌中铂抗性的驱动器。我们评估了帕唑帕尼和紫杉醇联合维持帕唑帕尼对铂耐药/难治性卵巢癌患者的疗效。整合素αvβ3和αvβ5在肿瘤相关脉管系统中均被上调。[18F] Fluciclatide是一种新型PET示踪剂，对整联蛋白αvβ3/ 5具有高度亲和力，可用于评估帕唑帕尼的抗血管生成作用。患者和方法我们对铂耐药/难治性卵巢癌患者进行了开放标签，Ib期研究。患者接受1周单药帕唑帕尼（每天800 mg），然后与每周紫杉醇（80 mg / m2）联合治疗。完成18周的联合治疗后，患者继续使用单药帕唑帕尼直至疾病进展。在Pazopanib的基线和1周后进行动态[18F] fluciclatide-PET成像。记录反应（RECIST 1.1），毒性和生存结果。通过治疗评估血管生成的循环标志物。结果意向性治疗分析包括14例患者。在七名患者（54％）中观察到完全和部分反应。中位无进展生存期（PFS）为10.63个月，总生存期（OS）为18.5个月。基线[18F]氟尿嘧啶摄取可预示长PFS。基线循环血管生成素和成纤维细胞生长因子（FGF）升高预示帕唑帕尼治疗后SUV60的降低更大。PET数据的动力学模型表明帕唑帕尼后K1和Ki降低，表明放射性配体的传递和保留降低。结论联合治疗后维持帕唑帕尼对铂类耐药/难治性卵巢癌有效且可耐受。[18F] Fluciclatide-PET的摄取参数可预测帕唑帕尼治疗的临床结局，表明抗血管生成反应。