Department of Medical Oncology and Experimental Therapeutics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
J Urol. 2015 Apr;193(4):1114-21. doi: 10.1016/j.juro.2014.09.110. Epub 2014 Oct 5.
Pazopanib has been assessed primarily in cytokine refractory or treatment naïve patients with metastatic renal cell carcinoma. Outcomes have been associated with a specific immunological profile. However, pazopanib activity in the third line setting and temporal changes in the immunological profile during therapy are poorly understood.
Study eligibility was limited to patients with 2 prior lines of therapy, including at least 1 vascular endothelial growth factor directed therapy, as well as ECOG performance status 0 to 2 and clear cell histology. Patients received pazopanib 800 mg daily. A Simon minmax 2-stage design was used with 80% power to determine an encouraging 23% overall response rate (10% type I error). Immunological profiles were assessed monthly on a Luminex® platform using the Human Cytokine 30-Plex Cytokine Immunoassay (Invitrogen™).
A total of 28 patients with a median age of 63 years (range 45 to 86) were enrolled in study. Of the patients 12 (43%) had a confirmed complete (1) or partial (11) response. In the cohort median progression-free survival was 16.5 months (95% CI 14.7-not reached). The most common grade 3/4 toxicities were hypertension (46% of cases) and proteinuria (14%). At 6 and 12 months responders had lower levels of HGF, VEGF, IL-6 and 8, and soluble IL-2R (each p <0.05). Nonresponders also showed increased numbers of myeloid-derived suppressor cells at each interval. Phenotypic and functional studies confirmed that the myeloid-derived suppressor cells were granulocytic.
Progression-free survival and the overall response rate associated with third line pazopanib were encouraging. Immunological profile differences between responders and nonresponders suggest that the mechanism of pazopanib resistance is at least partly related to the generation of systemic tumor immune tolerance.
帕唑帕尼主要在细胞因子难治或初治的转移性肾细胞癌患者中进行评估。结果与特定的免疫谱相关。然而，帕唑帕尼在三线治疗中的活性以及治疗过程中免疫谱的时间变化尚不清楚。
研究纳入标准仅限于接受过 2 线治疗的患者，其中至少有 1 线接受了血管内皮生长因子靶向治疗，ECOG 体能状态为 0 至 2 分，且组织学类型为透明细胞癌。患者接受帕唑帕尼 800mg/d。采用 Simon 最小最大两阶段设计，以 80%的功效确定了令人鼓舞的 23%的总缓解率（10%的Ⅰ类错误率）。每月在 Luminex®平台上使用 Human Cytokine 30-Plex Cytokine Immunoassay（Invitrogen™）评估免疫谱。
共纳入 28 例患者，中位年龄 63 岁（范围 45 岁至 86 岁）。患者中，12 例（43%）有确认的完全缓解（1 例）或部分缓解（11 例）。在该队列中，中位无进展生存期为 16.5 个月（95%CI 14.7-未达到）。最常见的 3/4 级毒性是高血压（46%的病例）和蛋白尿（14%）。在 6 个月和 12 个月时，缓解者的 HGF、VEGF、IL-6 和 8 以及可溶性 IL-2R 水平较低（均 p<0.05）。无应答者在每个时间点的髓源性抑制细胞数量也增加。表型和功能研究证实，髓源性抑制细胞是粒细胞。
帕唑帕尼三线治疗的无进展生存期和总缓解率令人鼓舞。缓解者和无应答者之间的免疫谱差异表明，帕唑帕尼耐药的机制至少部分与全身肿瘤免疫耐受的产生有关。
