Modulation of Premetastatic Niche by the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Localized High‐Risk Prostate Cancer Followed by Radical Prostatectomy: A Phase II Randomized Trial
Lessons Learned Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting. Pazopanib was safe and well tolerated without any new safety signals. Background Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid‐derived suppressor cells (VEGFR1+ MDS...
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Veröffentlicht in: | The oncologist (Dayton, Ohio) Ohio), 2018-12, Vol.23 (12), p.1413-e151 |
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Zusammenfassung: | Lessons Learned
Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting.
Pazopanib was safe and well tolerated without any new safety signals.
Background
Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid‐derived suppressor cells (VEGFR1+ MDSCs) potentially foster metastases by establishing a premetastatic niche. In a preclinical study, VEGFR1+ clustering in lymph nodes (LNs) independently predicted time to biochemical recurrence (TTBR) in localized prostate cancer . The hypothesis was that neoadjuvant pazopanib therapy will decrease VEGFR1+ clusters in pelvic lymph nodes and improve outcomes.
Methods
This is a phase II trial (NCT01832259) of neoadjuvant pazopanib 800 mg versus placebo daily for 4 weeks in high‐risk localized prostate cancer. The primary endpoint was a decrease in VEGFR1+ MDSC clustering assessed by immunohistochemistry (IHC) analysis. Secondary endpoints were safety, feasibility, and TTBR.
Results
Thirty patients were randomized to pazopanib versus placebo, with 15 patients randomized to each arm. Demographic and disease characteristics were similar in both arms. There was no difference in the VEGFR1+ clustering between the treatment arms (p = .345). Neoadjuvant therapy with pazopanib was well tolerated, and surgical complications were similar in both arms.
Conclusion
Neoadjuvant pazopanib therapy did not alter the premetastatic niche; however, treatment targeting vascular endothelial growth factor (VEGF) in the preoperative period was safe and feasible, which may open up the avenue to investigate novel combinatorial regimens, including a VEGF inhibitor in combination with immune checkpoint inhibitor in this setting.
摘要
背景。血管内皮生长因子受体 1 (VEGFR1)表达髓源性抑制细胞 (VEGFR1+ MDSC)可能会通过建立转移前微环境来促进转移。在一项临床前研究中,聚集在淋巴结 (LN) 中的 VEGFR1+独立预测出局限性前列腺癌的生化复发时间 (TTBR) [1]。我们的假设为,新辅助帕唑帕尼治疗将减少盆腔淋巴结中的 VEGFR1+ 细胞群,并改善预后。
方法。此试验为高危局限性前列腺癌的为期 4 周的新辅助帕唑帕尼 800 mg每日一次与安慰剂对比的II期试验 (NCT01832259)。主要终点是通过免疫组织化学 (IHC) 分析评估VEGFR1+ MDSC细胞群的减少情况。次要终点是安全性、可行性和 TTBR。
结果。将三十名患者随机分配到帕唑帕尼与安慰剂组,每组随机分配 15 名患者。两组患者在统计学和疾病特征方面相似。各治疗组间 VEGFR1+ 细胞群无差异 (p = 0.345)。使用帕唑帕尼的新辅助治疗耐受性良好,两组患者的外科并发症相似。
结论。新辅助帕唑帕尼治疗未改变转移前微环境;但是,术前阶段以血管内皮生长因子 (VEGF) 为靶点的治疗方案是安全可行的,这可能会为研究新式组合方案开辟一条通途,包括在此设定中联合使用 VEGF 抑制剂与免疫检查点抑制剂 |
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ISSN: | 1083-7159 1549-490X |
DOI: | 10.1634/theoncologist.2018-0652 |