Division of Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California, 101 The City Drive South, Bldg 56, Orange, Irvine, CA, 92868, USA.
Division of Surgical Oncology, Chao Family Comprehensive Cancer Center, University of California, 101 The City Drive South, Bldg 56, Orange, Irvine, CA, 92868, USA.
Cancer Chemother Pharmacol. 2018 Aug;82(2):353-360. doi: 10.1007/s00280-018-3624-6. Epub 2018 Jun 25.
This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.
Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.
The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.
The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.
本 II 期研究评估了帕唑帕尼（一种强效、多靶点的酪氨酸激酶抑制剂[TKI]，可抑制血管内皮生长因子受体[VEGFR]-1、-2 和 -3、血小板衍生生长因子受体[PDGFR]-α 和 -β 以及 cKit）与节拍式紫杉醇联合治疗转移性黑色素瘤患者的安全性和临床疗效。
60 例初治的化疗患者接受帕唑帕尼 800mg 每日一次治疗，联合节拍式紫杉醇 80mg/m2 每周三次，每 4 周为一个周期。主要终点为 6 个月无进展生存期（PFS）率，次要终点包括 1 年总生存率（OS）率、RECIST 缓解率、PFS 率和中位总生存期。允许患者既往接受 BRAF 靶向治疗或检查点抑制剂治疗。
6 个月 PFS 率为 68%，1 年 OS 率为 48%。客观缓解率为 37%，包括 1 例完全缓解和 20 例部分缓解。8 周时 32 例（55%）患者疾病稳定，总体临床获益率为 93%。6 个月时的中位 PFS 为 8 个月，中位 OS 为 12.7 个月。最常见（>15%）的非血液学、治疗相关不良事件为疲劳、腹泻、高血压、肝转氨酶升高和周围神经病。已知的一种类效应的治疗相关性肠穿孔发生在 1 例患者中。未观察到帕唑帕尼的血浆水平与疗效之间有显著关联。
帕唑帕尼联合节拍式紫杉醇治疗转移性黑色素瘤患者耐受性良好，疗效显著。值得进一步评估这种联合治疗方案。
